Publications by authors named "Lukas Kenner"

179 Publications

A modular self-adjuvanting cancer vaccine combined with an oncolytic vaccine induces potent antitumor immunity.

Nat Commun 2021 08 31;12(1):5195. Epub 2021 Aug 31.

Christian Doppler Laboratory for Viral Immunotherapy of Cancer, Medical University of Innsbruck, Innsbruck, Austria.

Functional tumor-specific cytotoxic T cells elicited by therapeutic cancer vaccination in combination with oncolytic viruses offer opportunities to address resistance to checkpoint blockade therapy. Two cancer vaccines, the self-adjuvanting protein vaccine KISIMA, and the recombinant oncolytic vesicular stomatitis virus pseudotyped with LCMV-GP expressing tumor-associated antigens, termed VSV-GP-TAA, both show promise as a single agent. Here we find that, when given in a heterologous prime-boost regimen with an optimized schedule and route of administration, combining KISIMA and VSV-GP-TAA vaccinations induces better cancer immunity than individually. Using several mouse tumor models with varying degrees of susceptibility for viral replication, we find that priming with KISIMA-TAA followed by VSV-GP-TAA boost causes profound changes in the tumor microenvironment, and induces a large pool of poly-functional and persistent antigen-specific cytotoxic T cells in the periphery. Combining this heterologous vaccination with checkpoint blockade further improves therapeutic efficacy with long-term survival in the spectrum. Overall, heterologous vaccination with KISIMA and VSV-GP-TAA could sensitize non-inflamed tumors to checkpoint blockade therapy.
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http://dx.doi.org/10.1038/s41467-021-25506-6DOI Listing
August 2021

A 23-Gene Classifier urine test for prostate cancer prognosis.

Clin Transl Med 2021 03;11(3):e340

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Urology Minimally Invasive Engineering Centre, Shenzhen, China.

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http://dx.doi.org/10.1002/ctm2.340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919118PMC
March 2021

Precision Medicine in Hematology 2021: Definitions, Tools, Perspectives, and Open Questions.

Hemasphere 2021 Mar 17;5(3):e536. Epub 2021 Feb 17.

Department of Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.

During the past few years, our understanding of molecular mechanisms and cellular interactions relevant to malignant blood cell disorders has improved substantially. New insights include a detailed knowledge about disease-initiating exogenous factors, endogenous (genetic, somatic, epigenetic) elicitors or facilitators of disease evolution, and drug actions and interactions that underlie efficacy and adverse event profiles in defined cohorts of patients. As a result, precision medicine and personalized medicine are rapidly growing new disciplines that support the clinician in making the correct diagnosis, in predicting outcomes, and in optimally selecting patients for interventional therapies. In addition, precision medicine tools are greatly facilitating the development of new drugs, therapeutic approaches, and new multiparametric prognostic scoring models. However, although the emerging roles of precision medicine and personalized medicine in hematology and oncology are clearly visible, several questions remain. For example, it remains unknown how precision medicine tools can be implemented in healthcare systems and whether all possible approaches are also affordable. In addition, there is a need to define terminologies and to relate these to specific and context-related tools and strategies in basic and applied science. To discuss these issues, a working conference was organized in September 2019. The outcomes of this conference are summarized herein and include a proposal for definitions, terminologies, and applications of precision and personalized medicine concepts and tools in hematologic neoplasms. We also provide proposals aimed at reducing costs, thereby making these applications affordable in daily practice.
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http://dx.doi.org/10.1097/HS9.0000000000000536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892291PMC
March 2021

An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma.

J Craniomaxillofac Surg 2021 Apr 5;49(4):312-316. Epub 2021 Feb 5.

Department of Otorhinolaryngology, Medical University of Vienna, Vienna, Austria.

Although mostly associated with good survival outcomes, some patients with HPV-positive oropharyngeal squamous cell carcinoma develop distant metastasis and face dire prognosis. The aim of this study was to analyze distant metastatic patients in regards to survival, clinical staging, therapy approach and p16/HPV status. This retrospective single-centre study assessed patients with HPV-associated oropharyngeal cancer with distant metastasis treated in a tertiary referral center from 2005 to 2019. Overall- (OS) and survival after diagnosis of distant metastasis (OMS), clinical staging and different therapy approaches were assessed. Moreover, the overall mortality was assessed, as well as the association of different therapy approaches and p16/HPV status with the survival outcome. Out of 211 patients with HPV-associated oropharyngeal cancer that were treated in the study period, 15 developed distant metastases (7.1%). Median OS and OMS of the total group were 11 months (range 0.1-32 months) and 3 months (range 0.1-21 months), respectively. The overall mortality rate was 53.3% (n = 8). Significantly better outcome was present in patients treated with primary chemoradiotherapy (median OS 17 months vs. not reached, p = .03, median OMS 8 months vs not reached, p = .05). The OMS was significantly better in patients treated with chemotherapy initially after diagnosis (mean OMS 21 months vs 4 months; P = .001). Surgical resection after initial diagnosis was associated with a significantly shorter OMS (median OMS 3 vs. 21 months, p = .005). Interestingly, postoperative adjuvant therapy was delayed in all of these cases due to surgical site complications. Systemic treatment after initial diagnosis may be beneficial in clinical outcome of HPV associated distant metastases. Furthermore, surgical site complications should be treated with immediate care in order to avoid delay of adjuvant therapy. Further studies are warranted for validation of our results.
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http://dx.doi.org/10.1016/j.jcms.2021.01.012DOI Listing
April 2021

Activation of NF-κB and p300/CBP potentiates cancer chemoimmunotherapy through induction of MHC-I antigen presentation.

Proc Natl Acad Sci U S A 2021 02;118(8)

Division of Medical Genetics, Health Sciences, Department of Biomedical Informatics, University of California San Diego, La Jolla, CA 92093.

Many cancers evade immune rejection by suppressing major histocompatibility class I (MHC-I) antigen processing and presentation (AgPP). Such cancers do not respond to immune checkpoint inhibitor therapies (ICIT) such as PD-1/PD-L1 [PD-(L)1] blockade. Certain chemotherapeutic drugs augment tumor control by PD-(L)1 inhibitors through potentiation of T-cell priming but whether and how chemotherapy enhances MHC-I-dependent cancer cell recognition by cytotoxic T cells (CTLs) is not entirely clear. We now show that the lysine acetyl transferases p300/CREB binding protein (CBP) control MHC-I AgPPM expression and neoantigen amounts in human cancers. Moreover, we found that two distinct DNA damaging drugs, the platinoid oxaliplatin and the topoisomerase inhibitor mitoxantrone, strongly up-regulate MHC-I AgPP in a manner dependent on activation of nuclear factor kappa B (NF-κB), p300/CBP, and other transcription factors, but independently of autocrine IFNγ signaling. Accordingly, NF-κB and p300 ablations prevent chemotherapy-induced MHC-I AgPP and abrogate rejection of low MHC-I-expressing tumors by reinvigorated CD8 CTLs. Drugs like oxaliplatin and mitoxantrone may be used to overcome resistance to PD-(L)1 inhibitors in tumors that had "epigenetically down-regulated," but had not permanently lost MHC-I AgPP activity.
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http://dx.doi.org/10.1073/pnas.2025840118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923353PMC
February 2021

YAP/TAZ inhibition reduces metastatic potential of Ewing sarcoma cells.

Oncogenesis 2021 Jan 8;10(1). Epub 2021 Jan 8.

Children's Cancer Research Institute, Zimmermannplatz 10, 1090, Vienna, Austria.

Ewing sarcoma (EwS) is a highly metastatic bone cancer characterized by the ETS fusion oncoprotein EWS-FLI1. EwS cells are phenotypically highly plastic and switch between functionally distinct cell states dependent on EWS-FLI1 fluctuations. Whereas EWS-FLI1 cells proliferate, EWS-FLI1 cells are migratory and invasive. Recently, we reported activation of MRTFB and TEAD, effectors of RhoA and Hippo signalling, upon low EWS-FLI1, orchestrating key steps of the EwS migratory gene expression program. TEAD and its co-activators YAP and TAZ are commonly overexpressed in cancer, providing attractive therapeutic targets. We find TAZ levels to increase in the migratory EWS-FLI1 state and to associate with adverse prognosis in EwS patients. We tested the effects of the potent YAP/TAZ/TEAD complex inhibitor verteporfin on EwS cell migration in vitro and on metastasis in vivo. Verteporfin suppressed expression of EWS-FLI1 regulated cytoskeletal genes involved in actin signalling to the extracellular matrix, effectively blocked F-actin and focal-adhesion assembly and inhibited EwS cell migration at submicromolar concentrations. In a mouse EwS xenograft model, verteporfin treatment reduced relapses at the surgical site and delayed lung metastasis. These data suggest that YAP/TAZ pathway inhibition may prevent EwS cell dissemination and metastasis, justifying further preclinical development of YAP/TAZ inhibitors for EwS treatment.
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http://dx.doi.org/10.1038/s41389-020-00294-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794350PMC
January 2021

The Implications of PDK1-4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance.

Front Oncol 2020 15;10:583217. Epub 2020 Dec 15.

Department of Pathology, Medical University of Vienna, Vienna, Austria.

A metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis-known as the Warburg effect-is characteristic for many cancers. It gives the cancer cells a survival advantage in the hypoxic tumor microenvironment and protects them from cytotoxic effects of oxidative damage and apoptosis. The main regulators of this metabolic shift are the pyruvate dehydrogenase complex and pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK is known to be overexpressed in several cancers and is associated with bad prognosis and therapy resistance. Whereas the expression of PDK1-3 is tissue specific, PDK4 expression is dependent on the energetic state of the whole organism. In contrast to other PDK isoforms, not only oncogenic, but also tumor suppressive functions of PDK4 have been reported. In tumors that profit from high OXPHOS and high fatty acid synthesis, PDK4 can have a protective effect. This is the case for prostate cancer, the most common cancer in men, and makes PDK4 an interesting therapeutic target. While most work is focused on PDK in tumors characterized by high glycolytic activity, little research is devoted to those cases where PDK4 acts protective and is therefore highly needed.
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http://dx.doi.org/10.3389/fonc.2020.583217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771695PMC
December 2020

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy.

Nature 2021 01 23;589(7842):442-447. Epub 2020 Dec 23.

Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna, Austria.

Successful pregnancies rely on adaptations within the mother, including marked changes within the immune system. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T cells through RANK in a manner that depends on AIRE medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T cells during pregnancy, and expand the functional role of maternal T cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.
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http://dx.doi.org/10.1038/s41586-020-03071-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116618PMC
January 2021

STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pathway.

Oncogene 2021 02 15;40(6):1091-1105. Epub 2020 Dec 15.

Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.

Metastatic melanoma is hallmarked by its ability of phenotype switching to more slowly proliferating, but highly invasive cells. Here, we tested the impact of signal transducer and activator of transcription 3 (STAT3) on melanoma progression in association with melanocyte inducing transcription factor (MITF) expression levels. We established a mouse melanoma model for deleting Stat3 in melanocytes with specific expression of human hyperactive NRAS in an Ink4a-deficient background, two frequent driver mutations in human melanoma. Mice devoid of Stat3 showed early disease onset with higher proliferation in primary tumors, but displayed significantly diminished lung, brain, and liver metastases. Whole-genome expression profiling of tumor-derived cells also showed a reduced invasion phenotype, which was further corroborated by 3D melanoma model analysis. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in the upregulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3-induced CAAT Box Enhancer Binding Protein (CEBP) expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that CEBPa/b binding to the MITF enhancer region silenced the MITF locus. Finally, by classification of patient-derived melanoma samples, we show that STAT3 and MITF act antagonistically and hence contribute differentially to melanoma progression. We conclude that STAT3 is a driver of the metastatic process in melanoma and able to antagonize MITF via direct induction of CEBP family member transcription.
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http://dx.doi.org/10.1038/s41388-020-01584-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116782PMC
February 2021

Transcription factors CP2 and YY1 as prognostic markers in head and neck squamous cell carcinoma: analysis of The Cancer Genome Atlas and a second independent cohort.

J Cancer Res Clin Oncol 2021 Mar 14;147(3):755-765. Epub 2020 Dec 14.

Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.

Purpose: The transcription factors YY1 and CP2 have been associated with tumor promotion and suppression in various cancers. Recently, simultaneous expression of both markers was correlated with negative prognosis in cancer. The aim of this study was to explore the expression of YY1 and CP2 in head and neck squamous cell carcinoma (HNSCC) patients and their association with survival.

Methods: First, we analyzed mRNA expression and copy number variations (CNVs) of YY1 and CP2 using "The Cancer Genome Atlas" (TCGA) with 510 HNSCC patients. Secondly, protein expression was investigated via immunohistochemistry in 102 patients, who were treated in the Vienna General Hospital, utilizing a tissue microarray.

Results: The median follow-up was 2.9 years (1.8-4.6) for the TCGA cohort and 10.3 years (6.5-12.8) for the inhouse tissue micro-array (TMA) cohort. The median overall survival of the TCGA cohort was decreased for patients with a high YY1 mRNA expression (4.0 vs. 5.7 years, p = 0.030, corr. p = 0.180) and high YY1-CNV (3.53 vs. 5.4 years, p = 0.0355, corr. p = 0.213). Furthermore, patients with a combined high expression of YY1 and CP2 mRNA showed a worse survival (3.5 vs. 5.4 years, p = 0.003, corr. p = 0.018). The mortality rate of patients with co-expression of YY1 and CP2 mRNA was twice as high compared to patients with low expression of one or both (HR 1.99, 95% CI 1.11-3.58, p = 0.021). Protein expression of nuclear YY1 and CP2 showed no association with disease outcome in our inhouse cohort.

Conclusion: Our data indicate that simultaneous expression of YY1 and CP2 mRNA is associated with shorter overall survival. Thus, combined high mRNA expression might be a suitable prognostic marker for risk stratification in HNSCC patients. However, since we could not validate this finding at genomic or protein level, we hypothesize that unknown underlying mechanisms which regulate mRNA transcription of YY1 and CP2 are the actual culprits leading to a worse survival.
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http://dx.doi.org/10.1007/s00432-020-03482-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872999PMC
March 2021

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK-driven lymphomagenesis.

Life Sci Alliance 2021 02 11;4(2). Epub 2020 Dec 11.

Department of Pathology, Medical University of Vienna, Vienna, Austria

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell-specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.
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http://dx.doi.org/10.26508/lsa.202000794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768196PMC
February 2021

Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up.

BMC Med 2020 12 1;18(1):376. Epub 2020 Dec 1.

Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.

Background: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies.

Methods: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy.

Results: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963-0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929-0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956-0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980-0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947-0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy.

Conclusions: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.
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http://dx.doi.org/10.1186/s12916-020-01834-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706045PMC
December 2020

Thyroid and androgen receptor signaling are antagonized by μ-Crystallin in prostate cancer.

Int J Cancer 2021 02 31;148(3):731-747. Epub 2020 Oct 31.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3'-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidences show a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein μ-Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRα/TRβ) in target tissues. We show in our study that low CRYM expression levels in PCa patients are associated with early biochemical recurrence and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in positron emission tomography/magnetic resonance imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3- and androgen-mediated signaling in PCa. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth.
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http://dx.doi.org/10.1002/ijc.33332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756625PMC
February 2021

Intact vitamin A transport is critical for cold-mediated adipose tissue browning and thermogenesis.

Mol Metab 2020 12 28;42:101088. Epub 2020 Sep 28.

Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: Transformation of white into brown fat ("browning") reduces obesity in many preclinical models and holds great promise as a therapeutic concept in metabolic disease. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue; however, the physiologic importance of systemic retinoid transport for adipose tissue browning and adaptive thermogenesis is unknown.

Methods: We performed cold exposure studies in mice and humans and used a genetic model of defective vitamin A transport, the retinol binding protein deficient (Rbp) mouse, to study the effects of cooling on systemic vitamin A and the relevance of intact retinoid transport on cold-induced adipose tissue browning.

Results: We show that cold stimulation in mice and humans leads to an increase in circulating retinol and its plasma transporter, Rbp. In Rbp mice, thermogenic programming of adipocytes and oxidative mitochondrial function are dramatically impaired in subcutaneous white fat, which renders Rbp mice more cold-sensitive. In contrast, retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In humans, cold-mediated retinol increase is associated with a shift in oxidative substrate metabolism suggestive of higher lipid utilisation.

Conclusions: Systemic vitamin A levels are regulated by cold exposure in mice and humans, and intact retinoid transport is essential for cold-induced adipose tissue browning and adaptive thermogenesis.
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http://dx.doi.org/10.1016/j.molmet.2020.101088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585949PMC
December 2020

Effects of Thyroid Function on Phosphodiester Concentrations in Skeletal Muscle and Liver: An In Vivo NMRS Study.

J Clin Endocrinol Metab 2020 12;105(12)

Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

Context: Thyroid function is clinically evaluated by determination of circulating concentrations of thyrotropin (thyroid-stimulating hormone; TSH) and free thyroxine (fT4). However, a tissue-specific effector substrate of thyroid function is lacking. Energy-rich phosphorus-containing metabolites (PM) and phospholipids (PL) might be affected by thyroid hormone action and can be noninvasively measured by 31P nuclear magnetic resonance spectroscopy (NMRS).

Objectives: To measure the actions of peripheral thyroid hormones on PM and PL tissue concentrations.

Design And Setting: A longitudinal, prospective pilot study was performed.

Participants: Nine patients with hyperthyroidism (HYPER) and 4 patients with hypothyroidism (HYPO) were studied at baseline and 3 months after treatment.

Main Outcome Measures: High-field 1H/31P NMRS was used to assess profiles of PM, PL, and flux through oxidative phosphorylase in liver and skeletal muscle, as well as ectopic tissue lipid content.

Results: The concentrations of total skeletal muscle (m-) and hepatic (h-) phosphodiesters (PDE) and one of the PDE constituents, glycerophosphocholine (GPC), were lower in HYPER compared with HYPO (m-PDE: 1.4 ± 0.4 mM vs 7.4 ± 3.5 mM, P = 0.003; m-GPC: 0.9 ± 0.3 mM vs 6.7 ± 3.5 mM, P = 0.003; h-PDE: 4.4 ± 1.4 mM vs 9.9 ± 3.9 mM, P = 0.012; h-GPC: 2.2 ± 1.0 mM vs 5.1 ± 2.4 mM, P = 0.024). Both h-GPC (rho = -0.692, P = 0.018) and h-GPE (rho = -0.633, P = 0.036) correlated negatively with fT4. In muscle tissue, a strong negative association between m-GPC and fT4 (rho = -0.754, P = 0.003) was observed.

Conclusions: Thyroxine is closely negatively associated with the PDE concentrations in liver and skeletal muscle. Normalization of thyroid dysfunction resulted in a decline of PDE in hypothyroidism and an increase in hyperthyroidism. Thus, PDE might be a sensitive tool to estimate tissue-specific peripheral thyroid hormone action.
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http://dx.doi.org/10.1210/clinem/dgaa663DOI Listing
December 2020

TYK2 licenses non-canonical inflammasome activation during endotoxemia.

Cell Death Differ 2021 02 14;28(2):748-763. Epub 2020 Sep 14.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, 1210, Vienna, Austria.

The non-canonical inflammasome is an emerging crucial player in the development of inflammatory and neurodegenerative diseases. It is activated by direct sensing of cytosolic lipopolysaccharide (LPS) by caspase-11 (CASP11), which then induces pyroptosis, an inflammatory form of regulated cell death. Here, we report that tyrosine kinase 2 (TYK2), a cytokine receptor-associated kinase, is a critical upstream regulator of CASP11. Absence of TYK2 or its kinase activity impairs the transcriptional induction of CASP11 in vitro and in vivo and protects mice from LPS-induced lethality. Lack of TYK2 or its enzymatic activity inhibits macrophage pyroptosis and impairs release of mature IL-1β and IL-18 specifically in response to intracellular LPS. Deletion of TYK2 in myeloid cells reduces LPS-induced IL-1β and IL-18 production in vivo, highlighting the importance of these cells in the inflammatory response to LPS. In support of our data generated with genetically engineered mice, pharmacological inhibition of TYK2 reduced LPS-induced upregulation of CASP11 in bone marrow-derived macrophages (BMDMs) and of its homolog CASP5 in human macrophages. Our study provides insights into the regulation of CASP11 in vivo and uncovered a novel link between TYK2 activity and CASP11-dependent inflammation.
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http://dx.doi.org/10.1038/s41418-020-00621-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862449PMC
February 2021

Paediatric Burkitt lymphoma patient-derived xenografts capture disease characteristics over time and are a model for therapy.

Br J Haematol 2021 01 3;192(2):354-365. Epub 2020 Sep 3.

Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.

Burkitt lymphoma (BL) accounts for almost two-thirds of all B-cell non-Hodgkin lymphoma (B-NHL) in children and adolescents and is characterised by a MYC translocation and rapid cell turnover. Intensive chemotherapeutic regimens have been developed in recent decades, including the lymphomes malins B (LMB) protocol, which have resulted in a survival rate in excess of 90%. Recent clinical trials have focused on immunochemotherapy, with the addition of rituximab to chemotherapeutic backbones, showing encouraging results. Despite these advances, relapse and refractory disease occurs in up to 10% of patients and salvage options for these carry a dismal prognosis. Efforts to better understand the molecular and functional characteristics driving relapse and refractory disease may help improve this prognosis. This study has established a paediatric BL patient-derived xenograft (PDX) resource which captures and maintains tumour heterogeneity, may be used to better characterise tumours and identify cell populations responsible for therapy resistance.
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http://dx.doi.org/10.1111/bjh.17043DOI Listing
January 2021

IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma.

Blood 2020 10;136(14):1657-1669

Department of Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.
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http://dx.doi.org/10.1182/blood.2019003793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530646PMC
October 2020

A New Strategy Toward B Cell-Based Cancer Vaccines by Active Immunization With Mimotopes of Immune Checkpoint Inhibitors.

Front Immunol 2020 27;11:895. Epub 2020 May 27.

Center for Pathophysiology, Infectiology and Immunology, Institute of Specific Prophylaxis and Tropical Medicine, Medical University of Vienna, Vienna, Austria.

Therapeutic monoclonal antibodies (mAbs), targeting tumor antigens, or immune checkpoints, have demonstrated a remarkable anti-tumor effect against various malignancies. However, high costs for mono- or combination therapies, associated with adverse effects or possible development of resistance in some patients, warrant further development and modification to gain more flexibility for this immunotherapy approach. An attractive alternative to passive immunization with therapeutic antibodies might be active immunization with mimotopes (B-cell peptides) representing the mAbs' binding epitopes, to activate the patient's own anti-tumor immune response following immunization. Here, we identified and examined the feasibility of inducing anti-tumor effects following active immunization with a mimotope of the immune checkpoint programmed cell death 1 (PD1), alone or in combination with a Her-2/neu B-cell peptide vaccine. Overlapping peptides spanning the extracellular domains of human PD1 (hPD1) were used to identify hPD1-derived mimotopes, using the therapeutic mAb Nivolumab as a proof of concept. Additionally, for evaluation in a tumor mouse model, a mouse PD1 (mPD1)-derived mimotope was identified using an anti-mPD1 mAb with mPD1/mPDL-1 blocking capacity. The identified mimotopes were characterized by assays, including a reporter cell-based assay, and their anti-tumor effects were evaluated in a syngeneic tumor mouse model stably expressing human Her-2/neu. The identified PD1-derived mimotopes were shown to significantly block the mAbs' capacity in inhibiting the respective PD1/PD-L1 interactions. A significant reduction in tumor growth was observed following active immunization with the mPD1-derived mimotope, associated with a significant reduction in proliferation and increased apoptotic rates in the tumors. Particularly, combined vaccination with the mPD1-derived mimotope and a multiple B-cell epitope Her-2/neu vaccine potentiated the vaccine's anti-tumor effect. Our results suggest active immunization with mimotopes of immune checkpoint inhibitors either as monotherapy or as combination therapy with tumor-specific vaccines, as a new strategy for cancer treatment.
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http://dx.doi.org/10.3389/fimmu.2020.00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266955PMC
April 2021

STAT5 is required for lipid breakdown and beta-adrenergic responsiveness of brown adipose tissue.

Mol Metab 2020 10 28;40:101026. Epub 2020 May 28.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210, Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090, Vienna, Austria. Electronic address:

Objective: Increasing energy expenditure through activation of brown adipose tissue (BAT) thermogenesis is an attractive approach to counteract obesity. It is therefore essential to understand the molecular mechanisms that control BAT functions. Until now several members of the Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway have been implicated as being relevant for BAT physiology. However, whether the STAT family member STAT5 is important for the thermogenic property of adipose tissues is unknown. Therefore, we have investigated the role of STAT5 in thermogenic fat in this paper.

Methods: We performed metabolic and molecular analyses using mice that harbor an adipocyte-specific deletion of Stat5a/b alleles.

Results: We found that STAT5 is necessary for acute cold-induced temperature maintenance and the induction of lipid mobilization in BAT following β-adrenergic stimulation. Moreover, mitochondrial respiration of primary differentiated brown adipocytes lacking STAT5 was diminished. Increased sensitivity to cold stress upon STAT5 deficiency was associated with reduced expression of thermogenic markers including uncoupling protein 1 (UCP1), while decreased stimulated lipolysis was linked to decreased protein kinase A (PKA) activity. Additionally, brown remodeling of white adipose tissue was diminished following chronic β-adrenergic stimulation, which was accompanied by a decrease in mitochondrial performance.

Conclusion: We conclude that STAT5 is essential for the functionality and the β-adrenergic responsiveness of thermogenic adipose tissue.
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http://dx.doi.org/10.1016/j.molmet.2020.101026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322099PMC
October 2020

IDO1 Paneth cells promote immune escape of colorectal cancer.

Commun Biol 2020 05 22;3(1):252. Epub 2020 May 22.

Institute of Cancer Research, Medical University of Vienna and Comprehensive Cancer Center, 1090, Vienna, Austria.

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1) Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1 Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1 Paneth cells as a target for immunotherapy.
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http://dx.doi.org/10.1038/s42003-020-0989-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244549PMC
May 2020

Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.

Haematologica 2021 06 1;106(6):1693-1704. Epub 2021 Jun 1.

Department of Paediatric Oncology, Addenbrooke Hospital, Cambridge, UK.

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.
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http://dx.doi.org/10.3324/haematol.2019.238766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168516PMC
June 2021

STAT3-dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer.

Mol Syst Biol 2020 04;16(4):e9247

Department of Analytical Chemistry, University of Vienna, Vienna, Austria.

Prostate cancer (PCa) has a broad spectrum of clinical behavior; hence, biomarkers are urgently needed for risk stratification. Here, we aim to find potential biomarkers for risk stratification, by utilizing a gene co-expression network of transcriptomics data in addition to laser-microdissected proteomics from human and murine prostate FFPE samples. We show up-regulation of oxidative phosphorylation (OXPHOS) in PCa on the transcriptomic level and up-regulation of the TCA cycle/OXPHOS on the proteomic level, which is inversely correlated to STAT3 expression. We hereby identify gene expression of pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging, and PSA level. Therefore, low PDK4 is a promising marker for PCa with dismal prognosis.
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http://dx.doi.org/10.15252/msb.20199247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178451PMC
April 2020

Epithelial stem cell marker LGR6 expression identifies a low-risk subgroup in human papillomavirus positive oropharyngeal squamous cell carcinoma.

Oral Oncol 2020 06 31;105:104657. Epub 2020 Mar 31.

Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.

Objectives: R-Spondins (RSPOs) and leucine-rich repeat-containing G-protein coupled receptors (LGRs) play a critical role in embryonic and cancer development through potentiation of WNT/ß-catenin signaling, but their prognostic significance in head and neck squamous cell carcinoma (HNSCC) is still unclear. HNSCC is a group of neoplasms that include, amongst others, oropharyngeal squamous cell carcinoma (OPSCC), some of which are induced by human papillomavirus (HPV). We aimed to investigate the potential prognostic value of RSPO2 and LGR4/5/6 on overall survival (OS) and disease-free survival (DFS) in HNSCC patients.

Methods: We examined RSPO and LGR expression by means of immunohistochemistry in 126 HNSCC patients. Furthermore, in order to validate our findings externally, we examined RSPO2 and LGR6 mRNA expression levels using independent secondary datasets.

Results: The five-year OS of our cohort was 59.6%. RSPO2 and LGR4/5/6 expression were not associated with OS or DFS in multivariable analyses. Within the HPV+ cases (n = 26, 33%), however, we observed a difference in OS by RSPO2 expression (5-year OS: RSPO+ 45.4% vs. RSPO2- 84.6%) and LGR6 expression (5-year OS: LGR6+ 52.9% vs. LGR6-100%). Evidence for an interaction of HPV status with RSPO2 and LGR6 was found for OS. Relative to HPV+/LGR6- patients, HPV+/LGR6+ patients were 12 times more likely to die. These results were replicated in the second dataset.

Conclusion: Our results indicated that the expression status of LGR6 had an influence on the aggressiveness of HPV+ OPSCC, potentially making this receptor a useful marker for identifying patients with a high risk of death.
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http://dx.doi.org/10.1016/j.oraloncology.2020.104657DOI Listing
June 2020

NSG mice humanized with allergen-specific T-cell lines as in vivo model of respiratory allergy.

Allergy 2020 08 3;75(8):2081-2084. Epub 2020 Apr 3.

Department of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology and Immunology, Medical University Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/all.14263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595002PMC
August 2020

The Determination of Immunomodulation and Its Impact on Survival of Rectal Cancer Patients Depends on the Area Comprising a Tissue Microarray.

Cancers (Basel) 2020 Feb 29;12(3). Epub 2020 Feb 29.

Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.

Background: T cell density in colorectal cancer (CRC) has proven to be of high prognostic importance. Here, we evaluated the influence of a hyperfractionated preoperative short-term radiation protocol (25 Gy) on immune cell density in tumor samples of rectal cancer (RC) patients and on patient survival. In addition, we assessed spatial tumor heterogeneity by comparison of analogue T cell quantification on full tissue sections with digital T cell quantification on a virtually established tissue microarray (TMA).

Methods: A total of 75 RC patients (60 irradiated, 15 treatment-naïve) were defined for retrospective analysis. RC samples were processed for immunohistochemistry (CD3, CD8, PD-1, PD-L1). Analogue (score 0-3) as well as digital quantification (TMA: 2 cores vs. 6 cores, mean T cell count) of marker expression in 2 areas (central tumor, CT; invasive margin, IM) was performed. Survival was estimated on the basis of analogue as well as digital marker densities calculated from 2 cores (Immunoscore: CD3/CD8 ratio) and 6 cores per tumor area.

Results: Irradiated RC samples showed a significant decrease in CD3 and CD8 positive T cells, independent of quantification mode. T cell densities of 6 virtual cores approximated to T cell densities of full tissue sections, independent of individual core density or location. Survival analysis based on full tissue section quantification demonstrated that CD3 and CD8 positive T cells as well as PD-1 positive tumor infiltrating leucocytes (TILs) in the CT and the IM had a significant impact on disease-free survival (DFS) as well as overall survival (OS). In addition, CD3 and CD8 positive T cells as well as PD-1 positive TILs in the IM proved as independent prognostic factors for DFS and OS; in the CT, PD-1 positive TILs predicted DFS and CD3 and CD8 positive T cells as well as PD-1 positive TILs predicted OS. Survival analysis based on virtual TMA showed no impact on DFS or OS.

Conclusion: Spatial tumor heterogeneity might result in inadequate quantification of immune marker expression; however, if using a TMA, 6 cores per tumor area and patient sample represent comparable amounts of T cell densities to those quantified on full tissue sections. Consistently, the tissue area used for immune marker quantification represents a crucial factor for the evaluation of prognostic and predictive biomarker potential.
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http://dx.doi.org/10.3390/cancers12030563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139832PMC
February 2020

Expression of inhibitors of apoptosis proteins in salivary gland adenoid cystic carcinoma: XIAP is an independent marker of impaired cause-specific survival.

Clin Otolaryngol 2020 05 5;45(3):364-369. Epub 2020 Feb 5.

Department of Otorhinolaryngology, Head and Neck Surgery, Medical University Vienna, Vienna, Austria.

Objectives: Inhibitors of apoptosis proteins are crucial to carcinogenesis since their expression results in evasion of apoptosis. Overexpression of inhibitors of apoptosis has repeatedly been associated with resistance to treatment and poor prognosis in various cancers. The role of inhibitors of apoptosis in adenoid cystic carcinoma of the salivary gland is still unclear. The aim of this study was to investigate the expression of inhibitors of apoptosis and their potential prognostic value in adenoid cystic carcinoma.

Design, Setting And Participants: Forty-nine patients, diagnosed with adenoid cystic carcinoma of the salivary gland between 1996 and 2016, were retrospectively included in this study. The expression of cIAP1, cIAP2, XIAP, Birc6, Livin and Survivin was assessed using immunohistochemistry, and their association of survival and prognosis was evaluated during a median follow-up of 6.4 years.

Main Outcome Measure: Cause-specific survival and recurrence-free survival rates.

Results: XIAP, cIAP2, Livin and nuclear Survivin showed high expression levels in adenoid cystic carcinoma in most patients. There was no significant association of cIAP1, cIAP2, Livin, Birc6 and Survivin with outcome. However, high XIAP expression was associated with worse cause-specific survival and worse response to radiotherapy and proved to be an independent marker in multivariable analysis.

Conclusion: Our data indicate that high expression of XIAP may be used as a prognosticator for poor survival and poor response to radiotherapy in adenoid cystic carcinoma patients.
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http://dx.doi.org/10.1111/coa.13509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317768PMC
May 2020

Overexpression of LAPTM4B-35 is a negative prognostic factor in head and neck squamous cell carcinoma.

Sci Rep 2019 12 11;9(1):18866. Epub 2019 Dec 11.

Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Overexpression of LAPTM4B-35 (lysosomal-associated transmembrane protein 4β-35) is associated with a poor prognosis in numerous malignant tumours. Expression patterns and effects of LAPTM4B-35 on head and neck squamous cell carcinomas (HNSCC) are unknown. The aim of this study was to investigate the prognostic relevance of LAPTM4B-35 in HNSCC. Tissue microarrays were constructed with primary tumours and associated lymph node metastases isolated from 127 patients. The expression of LAPTM4B-35 was investigated by immunohistochemistry and the results were correlated with survival data. LAPTM4B-35 in the primary tumour was highly expressed in 47.2% of the patients (60/127). LAPTM4B-35 expression was significantly associated with tumour stage. Moreover, overexpression of LAPTM4B-35 correlated with a significantly worse disease-free survival (10.23 years vs. not reached) and a higher recurrence rate (40.7% vs. 25%). High expression of LAPTM4B-35 in lymph node metastasis was found in 29.2% of cases. In 19.4% of cases, high LAPTM4B-35 expression was observed in both the primary tumour and corresponding lymph node metastases. In conclusion, our data indicates that overexpression of LAPTM4B-35 is associated with poor prognosis and may therefore serve as a new prognostic marker in HNSCC.
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http://dx.doi.org/10.1038/s41598-019-55319-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906383PMC
December 2019
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