Publications by authors named "Brendan J Jenkins"

68 Publications

IL-6 family cytokines in respiratory health and disease.

Cytokine 2021 Jul 16;143:155520. Epub 2021 Apr 16.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. Electronic address:

Chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis represent a major burden on healthcare systems with limited effective therapeutic options. Developing effective treatments for these debilitating diseases requires an understanding of how alterations at the molecular level affect lung macroscopic architecture. A common theme among these lung disorders is the presence of an underlying dysregulated immune system which can lead to sustained chronic inflammation. In this respect, several inflammatory cytokines have been implicated in the pathogenesis of lung diseases, thus leading to the notion that cytokines are attractive therapeutic targets for these disorders. In this review, we discuss and highlight the recent breakthroughs that have enhanced our understanding of the role of the interleukin (IL)-6 family of cytokines in lung homeostasis and chronic diseases including asthma, COPD, lung fibrosis and lung cancer.
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http://dx.doi.org/10.1016/j.cyto.2021.155520DOI Listing
July 2021

A Method for the Establishment of Human Lung Adenocarcinoma Patient-Derived Xenografts in Mice.

Methods Mol Biol 2021 ;2279:165-173

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.

Patient-derived xenografts (PDXs) are created by implanting human tumor tissue or cells into immunodeficent mice, and enable the study of tumor biology, biomarkers and response to therapy in vivo. This chapter describes a method for lung adenocarcinoma (LAC) PDX generation using subcutaneous implantation of tumor tissue and cell suspensions and incorporating the humanization of PDX models by reconstitution with human immune cells.
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http://dx.doi.org/10.1007/978-1-0716-1278-1_13DOI Listing
April 2021

Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2020 Dec 17;12(12). Epub 2020 Dec 17.

Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85719, USA.

: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. : Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. : Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. : Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.
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http://dx.doi.org/10.3390/cancers12123816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766822PMC
December 2020

ADAM17 Deficiency Protects against Pulmonary Emphysema.

Am J Respir Cell Mol Biol 2021 02;64(2):183-195

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Pulmonary emphysema is the major debilitating component of chronic obstructive pulmonary disease (COPD), which is a leading cause of morbidity and mortality worldwide. The ADAM17 (A disintegrin and metalloproteinase 17) protease mediates inflammation via ectodomain shedding of numerous proinflammatory cytokines, cytokine receptors, and adhesion molecules; however, its role in the pathogenesis of emphysema and COPD is poorly understood. This study aims to define the role of the protease ADAM17 in the pathogenesis of pulmonary emphysema. ADAM17 protein expression and activation was investigated in lung biopsies from patients with emphysema, as well as lungs of the emphysematous mouse model and an acute (4 d) cigarette smoke (CS)-induced lung pathology model. The mice, which display significantly reduced global ADAM17 expression, were coupled with emphysema-prone mice to produce :. Both and wild-type mice were subjected to acute CS exposure. Histological, immunohistochemical, immunofluorescence, and molecular analyses as well as lung function tests were performed to assess pulmonary emphysema, inflammation, and alveolar cell apoptosis. ADAM17 was hyperphosphorylated in the lungs of patients with emphysema and also in emphysematous and CS-exposed mice. ADAM17 deficiency ameliorated the development of pulmonary emphysema in mice by suppressing elevated alveolar cell apoptosis. In addition, genetic blockade of ADAM17 protected mice from CS-induced pulmonary inflammation and alveolar cell apoptosis. Our study places the protease ADAM17 as a central molecular switch implicated in the development of pulmonary emphysema, which paves the way for using ADAM17 inhibitors as potential therapeutic agents to treat COPD and emphysema.
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http://dx.doi.org/10.1165/rcmb.2020-0214OCDOI Listing
February 2021

Constitutive STAT3 Serine Phosphorylation Promotes Helicobacter-Mediated Gastric Disease.

Am J Pathol 2020 06 19;190(6):1256-1270. Epub 2020 Mar 19.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia. Electronic address:

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3 mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3 mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3 mice, which was associated with reduced proliferative potential of infected Stat3 gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3 mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2020.01.021DOI Listing
June 2020

STAT3-driven hematopoiesis and lymphopoiesis abnormalities are dependent on serine phosphorylation.

Cytokine 2020 Mar 19;130:155059. Epub 2020 Mar 19.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia. Electronic address:

Deregulated activation of the latent transcription factor STAT3 has been implicated in the pathogenesis of myeloproliferative and lymphoproliferative hematologic disorders. The uncontrolled activation of STAT3 has traditionally been assigned to its elevated phosphorylation at tyrosine 705 (pY) and associated nuclear transcriptional activity. By contrast, a transcriptional role for serine 727 phosphorylation (pS) of STAT3 has recently emerged, suggesting that pS may account for the pathological activity of STAT3 in certain disease settings. Here, by coupling pS-STAT3-deficient Stat3 mice with a STAT3-driven mouse model (gp130) for myeloproliferative and lymphoproliferative pathologies, we reveal a key role for pS-STAT3 in promoting multiple hematologic pathologies. The genetic blockade of pS-STAT3 in gp130:Stat3 mice ameliorated the neutrophilia, thrombocytosis, splenomegaly and lymphadenopathy that are features of gp130 mice. The protection against thrombocytosis in gp130:Stat3 mice coincided with normalized megakaryopoiesis in both bone marrow and spleen compartments. Interestingly, pS-STAT3-mediated abnormal lymphopoiesis in gp130 mice was more pronounced in lymph nodes compared to thymus, and was characterized by elevated numbers of B cells at the expense of T cells. Furthermore, pS-STAT3 dependency for these hematologic pathologies coincided with transcriptional activity on STAT3-regulated genes, rather than its effect on mitochondrial and metabolic genes. Collectively, these findings suggest that pS plays a critical pathological role in modulating the transcriptional activity of STAT3 in hematologic disorders.
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http://dx.doi.org/10.1016/j.cyto.2020.155059DOI Listing
March 2020

Innate Immune Molecule NLRC5 Protects Mice From Helicobacter-induced Formation of Gastric Lymphoid Tissue.

Gastroenterology 2020 07 10;159(1):169-182.e8. Epub 2020 Mar 10.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Victoria, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Victoria, Australia. Electronic address:

Background & Aims: Helicobacter pylori induces strong inflammatory responses that are directed at clearing the infection, but if not controlled, these responses can be harmful to the host. We investigated the immune-regulatory effects of the innate immune molecule, nucleotide-binding oligomerization domain-like receptors (NLR) family CARD domain-containing 5 (NLRC5), in patients and mice with Helicobacter infection.

Methods: We obtained gastric biopsies from 30 patients in Australia. We performed studies with mice that lack NLRC5 in the myeloid linage (Nlrc5) and mice without Nlrc5 gene disruption (controls). Some mice were gavaged with H pylori SS1 or Helicobacter felis; 3 months later, stomachs, spleens, and sera were collected, along with macrophages derived from bone marrow. Human and mouse gastric tissues and mouse macrophages were analyzed by histology, immunohistochemistry, immunoblots, and quantitative polymerase chain reaction. THP-1 cells (human macrophages, controls) and NLRC5 THP-1 cells (generated by CRISPR-Cas9 gene editing) were incubated with Helicobacter and gene expression and production of cytokines were analyzed.

Results: Levels of NLRC5 messenger RNA were significantly increased in gastric tissues from patients with H pylori infection, compared with patients without infection (P < .01), and correlated with gastritis severity (P < .05). H pylori bacteria induced significantly higher levels of chemokine and cytokine production by NLRC5 THP-1 macrophages than by control THP-1 cells (P < .05). After 3 months of infection with H felis, Nlrc5 mice developed gastric hyperplasia (P < .0001), splenomegaly (P < .0001), and increased serum antibody titers (P < .01), whereas control mice did not. Nlrc5 mice with chronic H felis infection had increased numbers of gastric B-cell follicles expressing CD19 (P < .0001); these follicles had features of mucosa-associated lymphoid tissue lymphoma. We identified B-cell-activating factor as a protein that promoted B-cell hyperproliferation in Nlrc5 mice.

Conclusions: NLRC5 is a negative regulator of gastric inflammation and mucosal lymphoid formation in response to Helicobacter infection. Aberrant NLRC5 signaling in macrophages can promote B-cell lymphomagenesis during chronic Helicobacter infection.
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http://dx.doi.org/10.1053/j.gastro.2020.03.009DOI Listing
July 2020

Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity.

Cancer Res 2019 10 3;79(20):5272-5287. Epub 2019 Sep 3.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Deregulated activation of the latent oncogenic transcription factor STAT3 in many human epithelial malignancies, including gastric cancer, has invariably been associated with its canonical tyrosine phosphorylation and enhanced transcriptional activity. By contrast, serine phosphorylation (pS) of STAT3 can augment its nuclear transcriptional activity and promote essential mitochondrial functions, yet the role of pS-STAT3 among epithelial cancers is ill-defined. Here, we reveal that genetic ablation of pS-STAT3 in the spontaneous gastric cancer mouse model and human gastric cancer cell line xenografts abrogated tumor growth that coincided with reduced proliferative potential of the tumor epithelium. Microarray gene expression profiling demonstrated that the suppressed gastric tumorigenesis in pS-STAT3-deficient mice associated with reduced transcriptional activity of STAT3-regulated gene networks implicated in cell proliferation and migration, inflammation, and angiogenesis, but not mitochondrial function or metabolism. Notably, the protumorigenic activity of pS-STAT3 aligned with its capacity to primarily augment RNA polymerase II-mediated transcriptional elongation, but not initiation, of STAT3 target genes. Furthermore, by using a combinatorial and proteomics approach based on the rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) assay, we identified RuvB-like AAA ATPase 1 (RUVBL1/Pontin) and enhancer of rudimentary homolog (ERH) as interacting partners of pS-STAT3 that are pivotal for its transcriptional activity on STAT3 target genes. Collectively, these findings uncover a hitherto unknown transcriptional role and obligate requirement for pS-STAT3 in gastric cancer that could be extrapolated to other STAT3-driven cancers. SIGNIFICANCE: These findings reveal a new transcriptional role and mandatory requirement for constitutive STAT3 serine phosphorylation in gastric cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0974DOI Listing
October 2019

ADAM17: An Emerging Therapeutic Target for Lung Cancer.

Cancers (Basel) 2019 Aug 21;11(9). Epub 2019 Aug 21.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.

Lung cancer is the leading cause of cancer-related mortality, which histologically is classified into small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all lung cancer diagnoses, with the majority of patients presenting with lung adenocarcinoma (LAC). mutations are a major driver of LAC, and are closely related to cigarette smoking, unlike mutations in the epidermal growth factor receptor (EGFR) which arise in never-smokers. Although the past two decades have seen fundamental progress in the treatment and diagnosis of NSCLC, NSCLC still is predominantly diagnosed at an advanced stage when therapeutic interventions are mostly palliative. A disintegrin and metalloproteinase 17 (ADAM17), also known as tumour necrosis factor-α (TNFα)-converting enzyme (TACE), is responsible for the protease-driven shedding of more than 70 membrane-tethered cytokines, growth factors and cell surface receptors. Among these, the soluble interleukin-6 receptor (sIL-6R), which drives pro-inflammatory and pro-tumourigenic IL-6 trans-signaling, along with several EGFR family ligands, are the best characterised. This large repertoire of substrates processed by ADAM17 places it as a pivotal orchestrator of a myriad of physiological and pathological processes associated with the initiation and/or progression of cancer, such as cell proliferation, survival, regeneration, differentiation and inflammation. In this review, we discuss recent research implicating ADAM17 as a key player in the development of LAC, and highlight the potential of ADAM17 inhibition as a promising therapeutic strategy to tackle this deadly malignancy.
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http://dx.doi.org/10.3390/cancers11091218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769596PMC
August 2019

The ADAM17 protease promotes tobacco smoke carcinogen-induced lung tumorigenesis.

Carcinogenesis 2020 06;41(4):527-538

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Lung cancer is the leading cause of cancer-related mortality, with most cases attributed to tobacco smoking, in which nicotine-derived nitrosamine ketone (NNK) is the most potent lung carcinogen. The ADAM17 protease is responsible for the ectodomain shedding of many pro-tumorigenic cytokines, growth factors and receptors, and therefore is an attractive target in cancer. However, the role of ADAM17 in promoting tobacco smoke carcinogen-induced lung carcinogenesis is unknown. The hypomorphic Adam17ex/ex mice-characterized by reduced global ADAM17 expression-were backcrossed onto the NNK-sensitive pseudo-A/J background. CRISPR-driven and inhibitor-based (GW280264X, and ADAM17 prodomain) ADAM17 targeting was employed in the human lung adenocarcinoma cell lines A549 and NCI-H23. Human lung cancer biopsies were also used for analyses. The Adam17ex/ex mice displayed marked protection against NNK-induced lung adenocarcinoma. Specifically, the number and size of lung lesions in NNK-treated pseudo-A/J Adam17ex/ex mice were significantly reduced compared with wild-type littermate controls. This was associated with lower proliferative index throughout the lung epithelium. ADAM17 targeting in A549 and NCI-H23 cells led to reduced proliferative and colony-forming capacities. Notably, among select ADAM17 substrates, ADAM17 deficiency abrogated shedding of the soluble IL-6 receptor (sIL-6R), which coincided with the blockade of sIL-6R-mediated trans-signaling via ERK MAPK cascade. Furthermore, NNK upregulated phosphorylation of p38 MAPK, whose pharmacological inhibition suppressed ADAM17 threonine phosphorylation. Importantly, ADAM17 threonine phosphorylation was significantly upregulated in human lung adenocarcinoma with smoking history compared with their cancer-free controls. Our study identifies the ADAM17/sIL-6R/ERK MAPK axis as a candidate therapeutic strategy against tobacco smoke-associated lung carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgz123DOI Listing
June 2020

ADAM17 selectively activates the IL-6 trans-signaling/ERK MAPK axis in KRAS-addicted lung cancer.

EMBO Mol Med 2019 04;11(4)

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Vic., Australia

Oncogenic mutations are major drivers of lung adenocarcinoma (LAC), yet the direct therapeutic targeting of KRAS has been problematic. Here, we reveal an obligate requirement by oncogenic KRAS for the ADAM17 protease in LAC In genetically engineered and xenograft (human cell line and patient-derived) -driven LAC models, the specific blockade of ADAM17, including with a non-toxic prodomain inhibitor, suppressed tumor burden by reducing cellular proliferation. The pro-tumorigenic activity of ADAM17 was dependent upon its threonine phosphorylation by p38 MAPK, along with the preferential shedding of the ADAM17 substrate, IL-6R, to release soluble IL-6R that drives IL-6 trans-signaling via the ERK1/2 MAPK pathway. The requirement for ADAM17 in -driven LAC was independent of bone marrow-derived immune cells. Furthermore, in mutant human LAC, there was a significant positive correlation between augmented phospho-ADAM17 levels, observed primarily in epithelial rather than immune cells, and activation of ERK and p38 MAPK pathways. Collectively, these findings identify ADAM17 as a druggable target for oncogenic -driven LAC and provide the rationale to employ ADAM17-based therapeutic strategies for targeting mutant cancers.
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http://dx.doi.org/10.15252/emmm.201809976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460353PMC
April 2019

Toll-like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2.

Int J Cancer 2019 06 7;144(12):3056-3069. Epub 2019 Jan 7.

Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Toll-like receptors (TLRs) play critical roles in host defense after recognition of conserved microbial- and host-derived components, and their dysregulation is a common feature of various inflammation-associated cancers, including gastric cancer (GC). Despite the recent recognition that metabolic reprogramming is a hallmark of cancer, the molecular effectors of altered metabolism during tumorigenesis remain unclear. Here, using bioenergetics function assays on human GC cells, we reveal that ligand-induced activation of TLR2, predominantly through TLR1/2 heterodimer, augments both oxidative phosphorylation (OXPHOS) and glycolysis, with a bias toward glycolytic activity. Notably, DNA microarray-based expression profiling of human cancer cells stimulated with TLR2 ligands demonstrated significant enrichment of gene-sets for oncogenic pathways previously implicated in metabolic regulation, including reactive oxygen species (ROS), p53 and Myc. Moreover, the redox gene encoding the manganese-dependent mitochondrial enzyme, superoxide dismutase (SOD)2, was strongly induced at the mRNA and protein levels by multiple signaling pathways downstream of TLR2, namely JAK-STAT3, JNK MAPK and NF-κB. Furthermore, siRNA-mediated suppression of SOD2 ameliorated the TLR2-induced metabolic shift in human GC cancer cells. Importantly, patient-derived tissue microarrays and bioinformatics interrogation of clinical datasets indicated that upregulated expression of TLR2 and SOD2 were significantly correlated in human GC, and the TLR2-SOD2 axis was associated with multiple clinical parameters of advanced stage disease, including distant metastasis, microvascular invasion and stage, as well as poor survival. Collectively, our findings reveal a novel TLR2-SOD2 axis as a potential biomarker for therapy and prognosis in cancer.
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http://dx.doi.org/10.1002/ijc.32060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590666PMC
June 2019

Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.

Gastroenterology 2019 03 30;156(4):1140-1155.e4. Epub 2018 Nov 30.

Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan; WPI Nano-Life Science Institute (Nano-LSI), Kanazawa University, Kanazawa, Japan. Electronic address:

Background & Aims: Gastritis is associated with development of stomach cancer, but little is known about changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression in epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice.

Methods: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b-knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan.

Results: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130 mice and patients compared with nontumor tissues. In gastric organoids and immortalized cell lines, expression of miR-135B was induced by interleukin 1 signaling. K19-C2mE mice with disruption of Mir-135b developed hyperplastic lesions that were 50% smaller than mice without Mir-135b disruption and had significant reductions in cell proliferation. Expression of miR-135B in gastric cancer cell lines increased their colony formation, migration, and sphere formation. We identified FOXN3 and RECK messenger RNAs (mRNAs) as targets of miR-135B; their knockdown reduced migration of gastric cancer cell lines. Levels of FOXN3 and RECK mRNAs correlated inversely with levels of miR-135B in human gastric tumors and in inflamed mucosa from K19-C2mE mice.

Conclusions: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors.
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http://dx.doi.org/10.1053/j.gastro.2018.11.059DOI Listing
March 2019

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer.

Nat Rev Immunol 2018 12;18(12):773-789

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.
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http://dx.doi.org/10.1038/s41577-018-0066-7DOI Listing
December 2018

Type IV Secretion System and Its Adhesin Subunit, CagL, Mediate Potent Inflammatory Responses in Primary Human Endothelial Cells.

Front Cell Infect Microbiol 2018 6;8:22. Epub 2018 Feb 6.

Infection & Immunity Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.

The Gram-negative bacterium, , causes chronic gastritis, peptic ulcers, and gastric cancer in humans. Although the gastric epithelium is the primary site of colonization, can gain access to deeper tissues. Concurring with this notion, has been found in the vicinity of endothelial cells in gastric submucosa. Endothelial cells play crucial roles in innate immune response, wound healing and tumorigenesis. This study examines the molecular mechanisms by which interacts with and triggers inflammatory responses in endothelial cells. We observed that infection of primary human endothelial cells stimulated secretion of the key inflammatory cytokines, interleukin-6 (IL-6) and interleukin-8 (IL-8). In particular, IL-8, a potent chemokine and angiogenic factor, was secreted by -infected endothelial cells to levels ~10- to 20-fold higher than that typically observed in -infected gastric epithelial cells. These inflammatory responses were triggered by the type IV secretion system (T4SS) and the T4SS-associated adhesin CagL, but not the translocation substrate CagA. Moreover, in contrast to integrin αβ playing an essential role in IL-8 induction by upon infection of gastric epithelial cells, both integrin αβ and integrin αβ were dispensable for IL-8 induction in -infected endothelial cells. However, epidermal growth factor receptor (EGFR) is crucial for mediating the potent -induced IL-8 response in endothelial cells. This study reveals a novel mechanism by which the T4SS and its adhesin subunit, CagL, may contribute to pathogenesis by stimulating the endothelial innate immune responses, while highlighting EGFR as a potential therapeutic target for controlling induced inflammation.
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http://dx.doi.org/10.3389/fcimb.2018.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808116PMC
January 2019

Hyperactive gp130/STAT3-driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development.

Int J Cancer 2018 07 19;143(1):167-178. Epub 2018 Feb 19.

Division of Infection and Immunity, Systems Immunity Research Institute, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.

Tertiary lymphoid structures (TLSs) display phenotypic and functional characteristics of secondary lymphoid organs, and often develop in tissues affected by chronic inflammation, as well as in certain inflammation-associated cancers where they are prognostic of improved patient survival. However, the mechanisms that govern the development of tumour-associated TLSs remain ill-defined. Here, we observed tumour-associated TLSs in a preclinical mouse model (gp130 ) of gastric cancer, where tumourigenesis is dependent on hyperactive STAT3 signalling through the common IL-6 family signalling receptor, gp130. Gastric tumourigenesis was associated with the development of B and T cell-rich submucosal lymphoid aggregates, containing CD21 cellular networks and high endothelial venules. Temporally, TLS formation coincided with the development of gastric adenomas and induction of homeostatic chemokines including Cxcl13, Ccl19 and Ccl21. Reflecting the requirement of gp130-driven STAT3 signalling for gastric tumourigenesis, submucosal TLS development was also STAT3-dependent, but independent of the cytokine IL-17 which has been linked with lymphoid neogenesis in chronic inflammation and autoimmunity. Interestingly, upregulated lymphoid chemokine expression and TLS formation were also observed in a chronic gastritis model induced by Helicobacter felis infection. Tumour-associated TLSs were also observed in patients with intestinal-type gastric cancer, and a gene signature linked with TLS development in gp130 mice was associated with advanced clinical disease, but was not prognostic of patient survival. Collectively, our in vivo data reveal that hyperactive gp130-STAT3 signalling closely links gastric tumourigenesis with lymphoid neogenesis, and while a TLS gene signature was associated with advanced gastric cancer in patients, it did not indicate a favourable prognosis.
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http://dx.doi.org/10.1002/ijc.31298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969244PMC
July 2018

Reviewing the Utility of EUS FNA to Advance Precision Medicine in Pancreatic Cancer.

Cancers (Basel) 2018 Jan 27;10(2). Epub 2018 Jan 27.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright St, Clayton, VIC 3168, Australia.

Advanced pancreatic cancer (PC) is an aggressive malignancy with few effective therapeutic options. While the evolution of precision medicine in recent decades has changed the treatment landscape in many cancers, at present no targeted therapies are used in the routine management of PC. Only a minority of patients with PC present with surgically resectable disease, and in the remainder obtaining high quality biopsy material for both diagnosis and molecular testing can prove challenging. Endoscopic ultrasound-guided fine needle aspiration (EUS FNA) is a widely used diagnostic procedure in PC, and allows tumour sampling in patients with both early and late stage disease. This review will provide an update on the role of EUS FNA as a diagnostic tool, as well as a source of genetic material which can be used both for molecular analysis and for the creation of valuable preclinical disease models. We will also consider relevant clinical applications of EUS FNA in the management of PC, and the path towards bringing precision medicine closer to the clinic in this challenging disease.
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http://dx.doi.org/10.3390/cancers10020035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836067PMC
January 2018

Clinical Utility of a STAT3-Regulated miRNA-200 Family Signature with Prognostic Potential in Early Gastric Cancer.

Clin Cancer Res 2018 03 12;24(6):1459-1472. Epub 2018 Jan 12.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined. miRNA microarrays were performed on gastric tissue from the preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in -based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response. Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family-regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone. Collectively, our discovery of a STAT3-regulated, miR-200 family-associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2485DOI Listing
March 2018

Immuno-detection of Immature and Bioactive Forms of the Inflammatory Cytokine IL-18.

Methods Mol Biol 2018 ;1725:229-235

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.

Gastric cancer (GC) is the third most lethal cancer worldwide, and like many other types of cancers, it is associated with precursory chronic inflammatory responses. In the context of many inflammation-associated cancers such as GC, activation of the innate immune response by infectious microbes and/or host-derived molecules is often characterized by production of the cytokines interleukin (IL)-1β and IL-18, which can often have divergent and opposing (i.e., pro or anti) roles in inflammation and oncogenesis. The processing of these mature bioactive cytokines from their inactive precursor polypeptides is dependent upon the enzyme Caspase-1, which is part of multiprotein complexes called "inflammasomes." Considering the recent mounting evidence for the role of IL-18 in the pathogenesis of GC, here, we describe a Western blotting technique used on genetic mouse models for GC to detect and characterize both pro-Il-18 and mature IL-18 proteins.
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http://dx.doi.org/10.1007/978-1-4939-7568-6_18DOI Listing
January 2019

Inflammasome Adaptor ASC Suppresses Apoptosis of Gastric Cancer Cells by an IL18-Mediated Inflammation-Independent Mechanism.

Cancer Res 2018 03 27;78(5):1293-1307. Epub 2017 Dec 27.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1β, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer. Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1887DOI Listing
March 2018

In vivo evidence that RBM5 is a tumour suppressor in the lung.

Sci Rep 2017 11 24;7(1):16323. Epub 2017 Nov 24.

The School of Biological Sciences, Monash University, 25 Rainforest Walk, Clayton, Victoria, 3800, Australia.

Cigarette smoking is undoubtedly a risk factor for lung cancer. Moreover, smokers with genetic mutations on chromosome 3p21.3, a region frequently deleted in cancer and notably in lung cancer, have a dramatically higher risk of aggressive lung cancer. The RNA binding motif 5 (RBM5) is one of the component genes in the 3p21.3 tumour suppressor region. Studies using human cancer specimens and cell lines suggest a role for RBM5 as a tumour suppressor. Here we demonstrate, for the first time, an in vivo role for RBM5 as a tumour suppressor in the mouse lung. We generated Rbm5 loss-of-function mice and exposed them to a tobacco carcinogen NNK. Upon exposure to NNK, Rbm5 loss-of-function mice developed lung cancer at similar rates to wild type mice. As tumourigenesis progressed, however, reduced Rbm5 expression lead to significantly more aggressive lung cancer i.e. increased adenocarcinoma nodule numbers and tumour size. Our data provide in vivo evidence that reduced RBM5 function, as occurs in a large number of patients, coupled with exposure to tobacco carcinogens is a risk factor for an aggressive lung cancer phenotype. These data suggest that RBM5 loss-of-function likely underpins at least part of the pro-tumourigenic consequences of 3p21.3 deletion in humans.
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http://dx.doi.org/10.1038/s41598-017-15874-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701194PMC
November 2017

Potential efficacy of interleukin-1β inhibition in lung cancer.

Lancet 2017 10 27;390(10105):1813-1814. Epub 2017 Aug 27.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, and Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Clayton, VIC 3168, Australia. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(17)32289-4DOI Listing
October 2017

Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumors.

Int J Cancer 2017 05 28;140(10):2331-2343. Epub 2017 Feb 28.

Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, 3800, Australia.

Pancreatic cancer (PC) is largely refractory to existing therapies used in unselected patient trials, thus emphasizing the pressing need for new approaches for patient selection in personalized medicine. KRAS mutations occur in 90% of PC patients and confer resistance to epidermal growth factor receptor (EGFR) inhibitors (e.g., panitumumab), suggesting that KRAS wild-type PC patients may benefit from targeted panitumumab therapy. Here, we use tumor tissue procured by endoscopic ultrasound-guided fine-needle aspirate (EUS-FNA) to compare the in vivo sensitivity in patient-derived xenografts (PDXs) of KRAS wild-type and mutant PC tumors to panitumumab, and to profile the molecular signature of these tumors in patients with metastatic or localized disease. Specifically, RNASeq of EUS-FNA-derived tumor RNA from localized (n = 20) and metastatic (n = 20) PC cases revealed a comparable transcriptome profile. Screening the KRAS mutation status of tumor genomic DNA obtained from EUS-FNAs stratified PC patients into either KRAS wild-type or mutant cohorts, and the engraftment of representative KRAS wild-type and mutant EUS-FNA tumor samples into NOD/SCID mice revealed that the growth of KRAS wild-type, but not mutant, PDXs was selectively suppressed with panitumumab. Furthermore, in silico transcriptome interrogation of The Cancer Genome Atlas (TCGA)-derived KRAS wild-type (n = 38) and mutant (n = 132) PC tumors revealed 391 differentially expressed genes. Taken together, our study validates EUS-FNA for the application of a novel translational pipeline comprising KRAS mutation screening and PDXs, applicable to all PC patients, to evaluate personalized anti-EGFR therapy in patients with KRAS wild-type tumors.
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http://dx.doi.org/10.1002/ijc.30648DOI Listing
May 2017

Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling.

Cytokine 2017 04 1;92:118-123. Epub 2017 Feb 1.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, Victoria 3168, Australia. Electronic address:

Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130 spontaneous model of GC to determine whether IL-11 trans-signalling promotes gastric tumourigenesis. sIL-11R protein was detectable in gastric tissue from GC patients, and sIL-11R levels were elevated in tumours of gp130 mice compared to matched non-tumours. Among candidate proteases associated with the generation of sIL-11R, ADAM10 and the related metalloprotease ADAM17 were significantly upregulated in tumours of both gp130 mice and GC patients compared to matched non-tumour tissues. The genetic blockade of IL-11 trans-signalling in gp130 mice upon the transgenic over-expression of the trans-signalling antagonist, sgp130Fc, failed to suppress gastric inflammation and associated tumour growth, and also had no effect on reducing hyper-activated STAT3 levels. Furthermore, a non-essential role for ADAM17 in IL-11-driven gastric tumourigenesis was supported by the observation that the tumour burden was unaffected in gp130:Adam17 mice in which ADAM17 expression levels have been substantially reduced. Collectively, these findings suggest that classic signalling rather than trans-signalling is the mode by which IL-11 promotes gastric tumourigenesis.
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http://dx.doi.org/10.1016/j.cyto.2017.01.015DOI Listing
April 2017

Transcriptional regulation of inflammasome-associated pattern recognition receptors, and the relevance to disease pathogenesis.

Mol Immunol 2017 06 30;86:3-9. Epub 2016 Sep 30.

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia; Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria 3800, Australia. Electronic address:

Over the last decade it has emerged that inflammasome complexes provide a pivotal platform for the host innate immune system to respond to exogenous infectious microbes (viruses, bacteria, fungi) and non-infectious environmental agents (cigarette smoke, pollution), as well as endogenous "danger" signals. Upon the canonical activation of inflammasomes, a key effector function is to catalyze, via caspase-1, the maturation of the potent pro-inflammatory cytokines interleukin (IL)-1β and IL-18, which, in addition to chronic inflammatory responses have also been intimately linked to the inflammatory form of lytic cell death, pyroptosis. However, recent evidence suggests that inflammasomes exhibit marked pleiotropism beyond their canonical functions, whereby their activation can also influence a large number of cellular responses including proliferation, apoptosis, autophagy and metabolism. It is therefore not surprising that the dysregulated expression and/or activation of inflammasomes is increasingly implicated in numerous disease states, such as chronic auto-inflammatory and autoimmune disorders, metabolic syndrome, neurodegenerative and cardiovascular diseases, as well as cancer. In this review we will highlight recent advancements in our understanding of the transcriptional regulation of genes encoding inflammasome-associated innate immune receptors, and the impact on a variety of cellular responses during disease pathogenesis.
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http://dx.doi.org/10.1016/j.molimm.2016.09.023DOI Listing
June 2017

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass.

J Biol Chem 2016 Oct 18;291(41):21703-21716. Epub 2016 Aug 18.

From the St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia,

Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are IL-6 family members with a wide range of biological functions. Human OSM (hOSM) and murine LIF (mLIF) act in mouse cells via a LIF receptor (LIFR)-glycoprotein 130 (gp130) heterodimer. In contrast, murine OSM (mOSM) signals mainly via an OSM receptor (OSMR)-gp130 heterodimer and binds with only very low affinity to mLIFR. hOSM and mLIF stimulate bone remodeling by both reducing osteocytic sclerostin and up-regulating the pro-osteoclastic factor receptor activator of NF-κB ligand (RANKL) in osteoblasts. In the absence of OSMR, mOSM still strongly suppressed sclerostin and stimulated bone formation but did not induce RANKL, suggesting that intracellular signaling activated by the low affinity interaction of mOSM with mLIFR is different from the downstream effects when mLIF or hOSM interacts with the same receptor. Both STAT1 and STAT3 were activated by mOSM in wild type cells or by mLIF/hOSM in wild type and Osmr cells. In contrast, in Osmr primary osteocyte-like cells stimulated with mOSM (therefore acting through mLIFR), microarray expression profiling and Western blotting analysis identified preferential phosphorylation of STAT3 and induction of its target genes but not of STAT1 and its target genes; this correlated with reduced phosphorylation of both gp130 and LIFR. In a mouse model of spontaneous osteopenia caused by hyperactivation of STAT1/3 signaling downstream of gp130 (gp130), STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signaling over STAT1 downstream of gp130 in this low bone mass condition, and this may have therapeutic value.
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http://dx.doi.org/10.1074/jbc.M116.748483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076839PMC
October 2016

Therapeutic Targeting of the IL-6 Trans-Signaling/Mechanistic Target of Rapamycin Complex 1 Axis in Pulmonary Emphysema.

Am J Respir Crit Care Med 2016 12;194(12):1494-1505

1 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.

Rationale: The potent immunomodulatory cytokine IL-6 is consistently up-regulated in human lungs with emphysema and in mouse emphysema models; however, the mechanisms by which IL-6 promotes emphysema remain obscure. IL-6 signals using two distinct modes: classical signaling via its membrane-bound IL-6 receptor (IL-6R), and trans-signaling via a naturally occurring soluble IL-6R.

Objectives: To identify whether IL-6 trans-signaling and/or classical signaling contribute to the pathogenesis of emphysema.

Methods: We used the gp130 genetic mouse model for spontaneous emphysema and cigarette smoke-induced emphysema models. Emphysema in mice was quantified by various methods including in vivo lung function and stereology, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay was used to assess alveolar cell apoptosis. In mouse and human lung tissues, the expression level and location of IL-6 signaling-related genes and proteins were measured, and the levels of IL-6 and related proteins in sera from emphysematous mice and patients were also assessed.

Measurements And Main Results: Lung tissues from patients with emphysema, and from spontaneous and cigarette smoke-induced emphysema mouse models, were characterized by excessive production of soluble IL-6R. Genetic blockade of IL-6 trans-signaling in emphysema mouse models and therapy with the IL-6 trans-signaling antagonist sgp130Fc ameliorated emphysema by suppressing augmented alveolar type II cell apoptosis. Furthermore, IL-6 trans-signaling-driven emphysematous changes in the lung correlated with mechanistic target of rapamycin complex 1 hyperactivation, and treatment of emphysema mouse models with the mechanistic target of rapamycin complex 1 inhibitor rapamycin attenuated emphysematous changes.

Conclusions: Collectively, our data reveal that specific targeting of IL-6 trans-signaling may represent a novel treatment strategy for emphysema.
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http://dx.doi.org/10.1164/rccm.201512-2368OCDOI Listing
December 2016

Multifaceted Role of IRAK-M in the Promotion of Colon Carcinogenesis via Barrier Dysfunction and STAT3 Oncoprotein Stabilization in Tumors.

Cancer Cell 2016 05;29(5):615-617

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC 3168, Australia; Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia. Electronic address:

Dysregulated interactions between the host immune system and gut microbiota can underpin inflammation, leading to colorectal cancer (CRC). In this issue of Cancer Cell, Kesselring et al. reveal a bimodal role of the TLR/IL-1R-signaling negative regulator, IRAK-M, in promoting tumoral microbial colonization and STAT3 oncoprotein stabilization during CRC.
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http://dx.doi.org/10.1016/j.ccell.2016.04.008DOI Listing
May 2016

Myeloid Differentiation Factor 88 Signaling in Bone Marrow-Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment.

Cancer Prev Res (Phila) 2016 Mar 17;9(3):253-63. Epub 2016 Feb 17.

Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.

It has been established that COX-2 and downstream signaling by prostaglandin E2 (PGE2) play a key role in tumorigenesis through generation of inflammatory microenvironment. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE2 pathway will be an effective preventive strategy for gastric cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0315DOI Listing
March 2016

Investigating the Role of Toll-Like Receptors in Mouse Models of Gastric Cancer.

Methods Mol Biol 2016 ;1390:427-49

Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Melbourne, VIC, Australia.

Gastric cancer (GC) is the second most lethal cancer world-wide, and the poor overall 5-year survival rate of <25 % for GC is largely due to both the late detection of this aggressive disease and limited effectiveness of current treatment options. Collectively, these observations underscore the need to identify new molecular targets (i.e., genes) to serve as biomarkers for early detection and/or treatment strategies to improve patient outcomes. While GC represents a growing number of cancers whereby deregulation of the immune system is linked to tumor initiation and progression, the identity of innate immune regulators with oncogenic potential in the host gastric mucosal epithelium remains obscure. Over the last couple of decades experimental mouse models for many cancer types have been widely used with great success to identify genes whose expression and/or mutation status influences tumorigenesis. Considering the recent mounting evidence for the role of innate immunity in the pathogenesis of inflammation-associated cancers such as GC, much attention has focused on members of the Toll-like receptor (TLR) family, which are key components of the innate immune system primarily known to trigger inflammatory responses upon pathogen detection. Here, we describe techniques used on genetic mouse models for GC to examine the role of specific TLR family members in the pathogenesis of GC.
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http://dx.doi.org/10.1007/978-1-4939-3335-8_25DOI Listing
October 2016