Publications by authors named "Valeria Poli"

99 Publications

Meta-Analysis of Microdissected Breast Tumors Reveals Genes Regulated in the Stroma but Hidden in Bulk Analysis.

Cancers (Basel) 2021 Jul 5;13(13). Epub 2021 Jul 5.

Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy.

Transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, sample heterogeneity, and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicates the interpretation of bulk transcriptomic profiles. To address these issues, we collected 48 microarray datasets derived from laser capture microdissected stroma or epithelium in breast tumors and performed a meta-analysis identifying robust lists of differentially expressed genes. This was used to create a database with carefully harmonized metadata that we make freely available to the research community. As predicted, combining the results of multiple datasets improved statistical power. Moreover, the separate analysis of stroma and epithelium allowed the identification of genes with different contributions in each compartment, which would not be detected by bulk analysis due to their distinct regulation in the two compartments. Our method can be profitably used to help in the discovery of biomarkers and the identification of functionally relevant genes in both the stroma and the epithelium. This database was made to be readily accessible through a user-friendly web interface.
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http://dx.doi.org/10.3390/cancers13133371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268805PMC
July 2021

Targeting the Extracellular HSP90 Co-Chaperone Morgana Inhibits Cancer Cell Migration and Promotes Anticancer Immunity.

Cancer Res 2021 Sep 30;81(18):4794-4807. Epub 2021 Jun 30.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.

HSP90 is secreted by cancer cells into the extracellular milieu, where it exerts protumoral activities by activating extracellular substrate proteins and triggering autocrine signals through cancer cell surface receptors. Emerging evidence indicates that HSP90 co-chaperones are also secreted and may direct HSP90 extracellular activities. In this study, we found that the HSP90 co-chaperone Morgana is released by cancer cells and, in association with HSP90, induces cancer cell migration through TLR2, TLR4, and LRP1. In syngeneic cancer mouse models, a mAb targeting Morgana extracellular activity reduced primary tumor growth via macrophage-dependent recruitment of CD8 T lymphocytes, blocked cancer cell migration, and inhibited metastatic spreading. Overall, these data define Morgana as a new player in the HSP90 extracellular interactome and suggest that Morgana may regulate HSP90 activity to promote cancer cell migration and suppress antitumor immunity. SIGNIFICANCE: This work suggests the potential therapeutic value of targeting the extracellular HSP90 co-chaperone Morgana to inhibit metastasis formation and enhance the CD8 T-cell-mediated antitumor immune response.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3150DOI Listing
September 2021

Two leading international congresses in Iran in the era of COVID-19: 21st royan international twin congress, 4th international and 16th Iranian genetics congress.

Bioessays 2021 06 7;43(6):e2100078. Epub 2021 Apr 7.

Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

In this report, we look at the challenges posed by the outbreak of COVID-19 and how the Executive Board of these two congresses succeeded in overcoming those challenges and holding two congresses. The approach for a large festival with different virtual setting components provided a suitable solution that led to exemplary achievements and created an appropriate model for future virtual or combined virtual and face-to-face events. These events proved that pandemic problems could not limit the organizers, pushing them to make better use of the facilities and turning this threat into an opportunity.
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http://dx.doi.org/10.1002/bies.202100078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250325PMC
June 2021

The N-terminal domain of the adaptor protein p140Cap interacts with Tiam1 and controls Tiam1/Rac1 axis.

Am J Cancer Res 2020 1;10(12):4308-4324. Epub 2020 Dec 1.

Department of Molecular Biotechnology and Health Sciences, University of Torino Torino 10126, Italy.

The p140Cap adaptor protein, encoded by the gene, negatively controls tumor progression, as demonstrated in the subgroup of -amplified breast cancers and in neuroblastoma patients, where high p140Cap expression predicts a decreased probability of developing metastasis, with a significantly prolonged survival. In NeuT mice, a preclinical model or Her2-positive breast cancer, we previously reported that p140Cap counteracts Her2-dependent breast cancer progression, associating with the specific Rac1 Guanine Nucleotide Exchange Factor, Tiam1, and limiting the activation of both Tiam1 and Rac1. Here, we show that in TUBO breast cancer cells derived from the NeuT tumors, p140Cap expression causes Tiam1 redistribution along the apicobasal junctional axis. Furthermore, p140Cap and Tiam1 interact with E-cadherin, a member of the adherence junction, with a concomitant increase of E-cadherin at the cell membrane. We characterized biochemically the interaction between p140Cap and Tiam1, showing that the amino terminal region of p140Cap (1-287 amino acids) is sufficient to associate with full length Tiam1, and with the truncated catalytic domain of Tiam1, with a concomitant decrease of the Tiam1 activity. Moreover, in a large cohort of Her2 positive breast cancer, high levels of expression positively correlates with increased survival in patients with high expression. Overall, our findings sustain a protective role of p140Cap in Her2 positive breast cancer, where p140Cap can associate with Tiam1 and negatively regulate the Tiam1/Rac1 axis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783762PMC
December 2020

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

Differential Co-Expression Analyses Allow the Identification of Critical Signalling Pathways Altered during Tumour Transformation and Progression.

Int J Mol Sci 2020 Dec 12;21(24). Epub 2020 Dec 12.

Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy.

Biological systems respond to perturbations through the rewiring of molecular interactions, organised in gene regulatory networks (GRNs). Among these, the increasingly high availability of transcriptomic data makes gene co-expression networks the most exploited ones. co-expression networks are useful tools to identify changes in response to an external perturbation, such as mutations predisposing to cancer development, and leading to changes in the activity of gene expression regulators or signalling. They can help explain the robustness of cancer cells to perturbations and identify promising candidates for targeted therapy, moreover providing higher specificity with respect to standard co-expression methods. Here, we comprehensively review the literature about the methods developed to assess differential co-expression and their applications to cancer biology. Via the comparison of normal and diseased conditions and of different tumour stages, studies based on these methods led to the definition of pathways involved in gene network reorganisation upon oncogenes' mutations and tumour progression, often converging on immune system signalling. A relevant implementation still lagging behind is the integration of different data types, which would greatly improve network interpretability. Most importantly, performance and predictivity evaluation of the large variety of mathematical models proposed would urgently require experimental validations and systematic comparisons. We believe that future work on differential gene co-expression networks, complemented with additional omics data and experimentally tested, will considerably improve our insights into the biology of tumours.
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http://dx.doi.org/10.3390/ijms21249461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764314PMC
December 2020

Liver-Specific siRNA-Mediated Stat3 or C3 Knockdown Improves the Outcome of Experimental Autoimmune Myocarditis.

Mol Ther Methods Clin Dev 2020 Sep 22;18:62-72. Epub 2020 May 22.

Department of Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, Torino 10126, Italy.

Myocarditis can lead to autoimmune disease, dilated cardiomyopathy, and heart failure, which is modeled in the mouse by cardiac myosin immunization (experimental autoimmune myocarditis [EAM]). Signal transducer and activator of transcription 3 (STAT3) systemic inhibition exerts both preventive and therapeutic effects in EAM, and STAT3 constitutive activation elicits immune-mediated myocarditis dependent on complement C3 and correlating with activation of the STAT3-interleukin 6 (IL-6) axis in the liver. Thus, liver-specific STAT3 inhibition may represent a therapeutic option, allowing to bypass the heart toxicity, predicted by systemic STAT3 inhibition. We therefore decided to explore the effectiveness of silencing liver Stat3 and C3 in preventing EAM onset and/or the recovery of cardiac functions. We first show that complement C3 and C5 genetic depletion significantly prevents the onset of spontaneous myocarditis, supporting the complement cascade as a viable target. In order to interfere with complement production and STAT3 activity specifically in the liver, we took advantage of liver-specific Stat3 or C3 small interfering (si)RNA nanoparticles, demonstrating that both siRNAs can significantly prevent myocarditis onset and improve the recovery of heart functions in EAM. Our data demonstrate that liver-specific Stat3/C3 siRNAs may represent a therapeutic option for autoimmune myocarditis and suggest that complement levels and activation might be predictive of progression to dilated cardiomyopathy.
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http://dx.doi.org/10.1016/j.omtm.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301178PMC
September 2020

The Microrna-143/145 Cluster in Tumors: A Matter of Where and When.

Cancers (Basel) 2020 Mar 17;12(3). Epub 2020 Mar 17.

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Turin, Italy.

The establishment and spreading of cancer involve the acquirement of many biological functions including resistance to apoptosis, enhanced proliferation and the ability to invade the surrounding tissue, extravasate from the primary site, survive in circulating blood, and finally extravasate and colonize distant organs giving origin to metastatic lesions, the major cause of cancer deaths. Dramatic changes in the expression of protein coding genes due to altered transcription factors activity or to epigenetic modifications orchestrate these events, intertwining with a microRNA regulatory network that is often disrupted in cancer cells. microRNAs-143 and -145 represent puzzling players of this game, with apparently contradictory functions. They were at first classified as tumor suppressive due to their frequently reduced levels in tumors, correlating with cell survival, proliferation, and migration. More recently, pro-oncogenic roles of these microRNAs have been described, challenging their simplistic definition as merely tumor-suppressive. Here we review their known activities in tumors, whether oncogenic or onco-suppressive, and highlight how their expression and functions are strongly dependent on their complex regulation downstream and upstream of cytokines and growth factors, on the cell type of expression and on the specific tumor stage.
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http://dx.doi.org/10.3390/cancers12030708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140083PMC
March 2020

The SRCIN1/p140Cap adaptor protein negatively regulates the aggressiveness of neuroblastoma.

Cell Death Differ 2020 02 8;27(2):790-807. Epub 2019 Jul 8.

Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy.

Neuroblastoma is the most common extra-cranial pediatric solid tumor, responsible for 13-15% of pediatric cancer death. Its intrinsic heterogeneity makes it difficult to target for successful therapy. The adaptor protein p140Cap/SRCIN1 negatively regulates tumor cell features and limits breast cancer progression. This study wish to assess if p140Cap is a key biological determinant of neuroblastoma outcome. RNAseq profiles of a large cohort of neuroblastoma patients show that SRCIN1 mRNA levels are an independent risk factor inversely correlated to disease aggressiveness. In high-risk patients, CGH+SNP microarray analysis of primary neuroblastoma identifies SRCIN1 as frequently altered by hemizygous deletion, copy-neutral loss of heterozygosity, or disruption. Functional experiments show that p140Cap negatively regulates Src and STAT3 signaling, affects anchorage-independent growth and migration, in vivo tumor growth and spontaneous lung metastasis formation. p140Cap also increases sensitivity of neuroblastoma cells to doxorubicin and etoposide treatment, as well as to a combined treatment with chemotherapy drugs and Src inhibitors. Our functional findings point to a causal role of p140Cap in curbing the aggressiveness of neuroblastoma, due to its ability to impinge on specific molecular pathways, and to sensitize cells to therapeutic treatment. This study provides the first evidence that the SRCIN1/p140Cap adaptor protein is a key player in neuroblastoma as a new independent prognostic marker for patient outcome and treatment. Altogether, these data highlight the potential clinical impact of SRCIN1/p140Cap expression in neuroblastoma tumors, in terms of reducing cytotoxic effects of chemotherapy, one of the main issues for pediatric tumor treatment.
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http://dx.doi.org/10.1038/s41418-019-0386-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205889PMC
February 2020

Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade.

Nat Commun 2019 06 19;10(1):2688. Epub 2019 Jun 19.

Nouscom Srl, Via Castel Romano 100, 00128, Rome, Italy.

Neoantigens (nAgs) are promising tumor antigens for cancer vaccination with the potential of inducing robust and selective T cell responses. Genetic vaccines based on Adenoviruses derived from non-human Great Apes (GAd) elicit strong and effective T cell-mediated immunity in humans. Here, we investigate for the first time the potency and efficacy of a novel GAd encoding multiple neoantigens. Prophylactic or early therapeutic vaccination with GAd efficiently control tumor growth in mice. In contrast, combination of the vaccine with checkpoint inhibitors is required to eradicate large tumors. Gene expression profile of tumors in regression shows abundance of activated tumor infiltrating T cells with a more diversified TCR repertoire in animals treated with GAd and anti-PD1 compared to anti-PD1. Data suggest that effectiveness of vaccination in the presence of high tumor burden correlates with the breadth of nAgs-specific T cells and requires concomitant reversal of tumor suppression by checkpoint blockade.
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http://dx.doi.org/10.1038/s41467-019-10594-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584502PMC
June 2019

Where Sin3a Meets STAT3: Balancing STAT3-Mediated Transcriptional Activation and Repression.

Cancer Res 2019 06;79(12):3031-3033

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.

STAT3 can mediate epigenetic silencing of tumor suppressor genes (TSG). However, little is known about the molecular mechanisms involved, except that this action is mediated by DNA methylation and requires STAT3 acetylation. In this issue of , Gambi and colleagues confirm that oncogene-driven constitutive STAT3 acetylation is responsible for TSG silencing. Furthermore, they show that the Sin3a transcriptional repressor complex is an obligatory partner of STAT3 on the promoters of the repressed genes, shedding light on the mechanisms involved in STAT3-mediated transcriptional repression, and more importantly, identifying that the STAT3-Sin3a axis is a potential selective therapeutic target in STAT3-dependent tumors..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0927DOI Listing
June 2019

SP1 and STAT3 Functionally Synergize to Induce the Small GTPase and a Subclass of Non-canonical WNT Responsive Genes Correlating with Poor Prognosis in Breast Cancer.

Cancers (Basel) 2019 Jan 16;11(1). Epub 2019 Jan 16.

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Turin, Italy.

Breast cancer is a heterogeneous disease whose clinical management is very challenging. Although specific molecular features characterize breast cancer subtypes with different prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical Wingless-type MMTV Integration site (WNT) and the Signal Transducer and Activator of Transcription (STAT)3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase Ras Homolog Family Member U . Here we show that transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of c-JUN N-terminal kinase (JNK) and the recruitment of the Specificity Protein 1 (SP1) transcription factor to the promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors leads to impaired migration and invasion in basal-like MDA-MB-231 and BT-549 cells, suggesting that STAT3 and SP1 can cooperate to induce high expression and enhance breast cancer cells migration. Moreover, in vivo concomitant binding of STAT3 and SP1 defines a subclass of genes belonging to the non-canonical WNT and the Interleukin (IL)-6/STAT3 pathways and contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators.
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http://dx.doi.org/10.3390/cancers11010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356433PMC
January 2019

Lysosomal protease deficiency or substrate overload induces an oxidative-stress mediated STAT3-dependent pathway of lysosomal homeostasis.

Nat Commun 2018 12 17;9(1):5343. Epub 2018 Dec 17.

Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.

Diverse cellular processes depend on the lysosomal protease system but how cells regulate lysosomal proteolytic capacity is only partly understood. We show here that cells can respond to protease/substrate imbalance in this compartment by de novo expression of multiple lysosomal hydrolases. This response, exemplified here either by loss of asparagine endopeptidase (AEP) or other lysosomal cysteine proteases, or by increased endocytic substrate load, is not dependent on the transcription factor EB (TFEB) but rather is triggered by STAT3 activation downstream of lysosomal oxidative stress. Similar lysosomal adaptations are seen in mice and cells expressing a constitutively active form of STAT3. Our results reveal how cells can increase lysosomal protease capacity under 'fed' rather than 'starved' conditions that activate the TFEB system. In addition, STAT3 activation due to lysosomal stress likely explains the hyperproliferative kidney disease and splenomegaly observed in AEP-deficient mice.
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http://dx.doi.org/10.1038/s41467-018-07741-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297226PMC
December 2018

Nucleus, Mitochondrion, or Reticulum? STAT3 à La Carte.

Int J Mol Sci 2018 Sep 18;19(9). Epub 2018 Sep 18.

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Turin, Italy.

The transcription factor signal transducer and activator of transcription (STAT)3 mediates the functions of cytokines, growth factors, and oncogenes under both physiological and pathological conditions. Uncontrolled/constitutive STAT3 activity is often detected in tumors of different types, where its role is mostly that of an oncogene, contributing in multiple ways to tumor transformation, growth, and progression. For this reason, many laboratories and pharmaceutical companies are making efforts to develop specific inhibitors. However, STAT3 has also been shown to act as a tumor suppressor in a number of cases, suggesting that its activity is strongly context-specific. Here, we discuss the bases that can explain the multiple roles of this factor in both physiological and pathological contexts. In particular, we focus on the following four features: (i) the distinct properties of the STAT3α and β isoforms; (ii) the multiple post-translational modifications (phosphorylation on tyrosine or serine, acetylation and methylation on different residues, and oxidation and glutathionylation) that can affect its activities downstream of multiple different signals; (iii) the non-canonical functions in the mitochondria, contributing to the maintenance of energy homeostasis under stress conditions; and (iv) the recently discovered functions in the endoplasmic reticulum, where STAT3 contributes to the regulation of calcium homeostasis, energy production, and apoptosis.
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http://dx.doi.org/10.3390/ijms19092820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164042PMC
September 2018

STAT3 localizes to the ER, acting as a gatekeeper for ER-mitochondrion Ca fluxes and apoptotic responses.

Cell Death Differ 2019 05 24;26(5):932-942. Epub 2018 Jul 24.

Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126, Torino, Italy.

STAT3 is an oncogenic transcription factor exerting its functions both as a canonical transcriptional activator and as a non-canonical regulator of energy metabolism and mitochondrial functions. While both activities are required for cell transformation downstream of different oncogenic stimuli, they rely on different post-translational activating events, namely phosphorylation on either Y705 (nuclear activities) or S727 (mitochondrial functions). Here, we report the discovery of the unexpected STAT3 localization to the endoplasmic reticulum (ER), from where it modulates ER-mitochondria Ca release by interacting with the Ca channel IP3R3 and facilitating its degradation. The release of Ca is of paramount importance for life/death cell decisions, as excessive Ca causes mitochondrial Ca overload, the opening of the mitochondrial permeability transition pore, and the initiation of the intrinsic apoptotic program. Indeed, STAT3 silencing enhances ER Ca release and sensitivity to apoptosis following oxidative stress in STAT3-dependent mammary tumor cells, correlating with increased IP3R3 levels. Accordingly, basal-like mammary tumors, which frequently display constitutively active STAT3, show an inverse correlation between IP3R3 and STAT3 protein levels. These results suggest that STAT3-mediated IP3R3 downregulation in the ER crucially contributes to its anti-apoptotic functions via modulation of Ca fluxes.
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http://dx.doi.org/10.1038/s41418-018-0171-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214529PMC
May 2019

Author Correction: STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

Nat Med 2018 Sep;24(9):1481

Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

In the version of this article originally published, the names of three authors were incorrect. The authors were listed as "Coral Fustero-Torres", "Elena Pineiro" and "Melchor Sánchez-Martínez". Their respective names are "Coral Fustero-Torre", "Elena Piñeiro-Yáñez" and "Melchor Sanchez-Martinez". The errors have been corrected in the print, HTML and PDF versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0108-5DOI Listing
September 2018

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

Nat Med 2018 07 11;24(7):1024-1035. Epub 2018 Jun 11.

Brain Metastasis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.
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http://dx.doi.org/10.1038/s41591-018-0044-4DOI Listing
July 2018

Psoriasis: A STAT3-Centric View.

Int J Mol Sci 2018 Jan 6;19(1). Epub 2018 Jan 6.

Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.

Signal Transducer and Activator of Transcription (STAT)3 has recently emerged as a key player in the development and pathogenesis of psoriasis and psoriatic-like inflammatory conditions. Indeed, STAT3 hyperactivation has been reported in virtually every cell type involved in disease initiation and maintenance, and this factor mediates the signal of most cytokines that are involved in disease pathogenesis, including the central Interleukin (IL)-23/IL-17/IL-22 axis. Despite the recent availability of effective biological agents (monoclonal antibodies) against IL-17 and IL-23, which have radically changed the current standard of disease management, the possibility of targeting either STAT3 itself or, even better, the family of upstream activators Janus kinases (JAK1, 2, 3, and TYK2) offers additional therapeutic options. Due to the oral/topical administration modality of these small molecule drugs, their lower cost, and the reduced risk of eliciting adverse immune responses, these compounds are being actively scrutinized in clinical settings. Here, we summarize the main pathological features of psoriatic conditions that provide the rationale for targeting the JAK/STAT3 axis in disease treatment.
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http://dx.doi.org/10.3390/ijms19010171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796120PMC
January 2018

MicroRNAs-143 and -145 induce epithelial to mesenchymal transition and modulate the expression of junction proteins.

Cell Death Differ 2017 10 23;24(10):1750-1760. Epub 2017 Jun 23.

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Turin, Italy.

Transforming growth factor (TGF)-β is one of the major inducers of epithelial to mesenchymal transition (EMT), a crucial program that has a critical role in promoting carcinoma's metastasis formation. MicroRNAs-143 and -145, which are both TGF-β direct transcriptional targets, are essential for the differentiation of vascular smooth muscle cells (VSMC) during embryogenesis, a TGF-β-dependent process reminiscent of EMT. Their role in adult tissues is however less well defined and even ambiguous, as their expression was correlated both positively and negatively with tumor progression. Here we show that high expression of both miRs-143 and -145 in mouse mammary tumor cells expressing constitutively active STAT3 (S3C) is involved in mediating their disrupted cell-cell junctions. Additionally, miR-143 appears to have a unique role in tumorigenesis by enhancing cell migration in vitro and extravasation in vivo while impairing anchorage-independent growth, which may explain the contradictory reports about its role in tumors. Accordingly, we demonstrate that overexpression of either miRNA in the non-transformed mammary epithelial NMuMG cells leads to upregulation of EMT markers and of several endogenous TGF-β targets, downmodulation of a number of junction proteins and increased motility, correlating with enhanced basal and TGF-β-induced SMAD-mediated transcription. Moreover, pervasive transcriptome perturbation consistent with the described phenotype was observed. In particular, the expression of several transcription factors involved in the mitogenic responses, of MAPK family members and, importantly, of several tight junction proteins and the SMAD co-repressor TGIF was significantly reduced. Our results provide important mechanistic insight into the non-redundant role of miRs-143 and -145 in EMT-related processes in both transformed and non-transformed cells, and suggest that their expression must be finely coordinated to warrant optimal migration/invasion while not interfering with cell growth.
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http://dx.doi.org/10.1038/cdd.2017.103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596419PMC
October 2017

STAT3 in cancer: A double edged sword.

Cytokine 2017 10 31;98:42-50. Epub 2017 May 31.

Molecular Biotechnology Center, Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, 10126 Turin, Italy. Electronic address:

The transcription factor signal transducer and activator of transcription (STAT) 3 is activated downstream of cytokines, growth factors and oncogenes to mediate their functions under both physiological and pathological conditions. In particular, aberrant/unrestrained STAT3 activity is detected in a wide variety of tumors, driving multiple pro-oncogenic functions. For that, STAT3 is widely considered as an oncogene and is the object of intense translational studies. One of the distinctive features of this factor is however, its ability to elicit different and sometimes contrasting effects under different conditions. In particular, STAT3 activities have been shown to be either pro-oncogenic or tumor-suppressive according to the tumor aetiology/mutational landscape, suggesting that the molecular bases underlining its functions are still incompletely understood. Here we discuss some of the properties that may provide the bases to explain STAT3 heterogeneous functions, and in particular how post-translational modifications contribute shaping its sub-cellular localization and activities, the cross talk between these activities and cell metabolic conditions, and finally how its functions can control the behaviour of both tumor and tumor microenvironment cell populations.
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http://dx.doi.org/10.1016/j.cyto.2017.03.018DOI Listing
October 2017

STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration.

J Neurosci 2017 04 20;37(16):4255-4269. Epub 2017 Mar 20.

Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom,

After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population. Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery.
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http://dx.doi.org/10.1523/JNEUROSCI.3481-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413174PMC
April 2017

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis.

J Mol Med (Berl) 2017 01 27;95(1):109-117. Epub 2016 Aug 27.

Institute of Cancer Research, Medical University of Vienna & Comprehensive Cancer Center (CCC), Vienna, Austria.

We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3) aggravated liver damage and fibrosis in the Mdr2 (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3 Mdr2 mice but the functional consequences of these processes in cholestatic liver injury remained unclear. Here, we show normal canalicular architecture and bile flow but increased amounts of bile acids in the bile of STAT3 Mdr2 mice. Moreover, STAT3-deficient hepatocytes displayed increased sensitivity to bile acid-induced apoptosis in vitro. Since EGFR signaling has been reported to protect hepatocytes from bile acid-induced apoptosis, we generated mice with hepatocyte/cholangiocyte-specific ablation of EGFR (EGFR) and crossed them to Mdr2 mice. Importantly, deletion of EGFR phenocopied deletion of STAT3 and led to aggravated liver damage, liver fibrosis, and hyperproliferation of K19 cholangiocytes. Our data demonstrate hepatoprotective functions of the STAT3-EGFR signaling axis in cholestatic liver disease.

Key Message: STAT3 is a negative regulator of bile acid biosynthesis. STAT3 protects from bile acid-induced apoptosis and regulates EGFR expression. EGFR signaling protects from cholestatic liver injury and fibrosis.
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http://dx.doi.org/10.1007/s00109-016-1462-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225179PMC
January 2017

Ablation of STAT3 in the B Cell Compartment Restricts Gammaherpesvirus Latency In Vivo.

mBio 2016 08 2;7(4). Epub 2016 Aug 2.

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA

Unlabelled: A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. Many cancers, including those associated with members of the gammaherpesvirus family, Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, express elevated levels of active host signal transducer and activator of transcription-3 (STAT3). STAT3 is activated by tyrosine phosphorylation in response to many cytokines and can orchestrate effector responses that include proliferation, inflammation, metastasis, and developmental programming. However, the contribution of STAT3 to gammaherpesvirus pathogenesis remains to be completely understood. This is the first study to have identified STAT3 as a critical host determinant of the ability of gammaherpesvirus to establish long-term latency in an animal model of disease. Following an acute infection, murine gammaherpesvirus 68 (MHV68) established latency in resident B cells, but establishment of latency was dramatically reduced in animals with a B cell-specific STAT3 deletion. The lack of STAT3 in B cells did not impair germinal center responses for immunoglobulin (Ig) class switching in the spleen and did not reduce either total or virus-specific IgG titers. Although ablation of STAT3 in B cells did not have a global effect on these assays of B cell function, it had long-term consequences for the viral load of the host, since virus latency was reduced at 6 to 8 weeks postinfection. Our findings establish host STAT3 as a mediator of gammaherpesvirus persistence.

Importance: The insidious ability of gammaherpesviruses to establish latent infections can have detrimental consequences for the host. Identification of host factors that promote viral latency is essential for understanding latency mechanisms and for therapeutic interventions. We provide the first evidence that STAT3 expression is needed for murine gammaherpesvirus 68 to establish latency in primary B cells during an active immune response to infection. STAT3 deletion in B cells does not impair adaptive immune control of the virus, but loss of STAT3 in B cells has a long-lasting impact on viral persistence. These results indicate a potential therapeutic benefit of STAT3 inhibitors for combating gammaherpesvirus latency and, thereby, associated pathologies.
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http://dx.doi.org/10.1128/mBio.00723-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981709PMC
August 2016

Stat3 Controls Tubulointerstitial Communication during CKD.

J Am Soc Nephrol 2016 Dec 6;27(12):3690-3705. Epub 2016 May 6.

Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Descartes, Institut Necker Enfants Malades, Department of Growth and Signaling,

In CKD, tubular cells may be involved in the induction of interstitial fibrosis, which in turn, leads to loss of renal function. However, the molecular mechanisms that link tubular cells to the interstitial compartment are not clear. Activation of the Stat3 transcription factor has been reported in tubular cells after renal damage, and Stat3 has been implicated in CKD progression. Here, we combined an experimental model of nephron reduction in mice from different genetic backgrounds and genetically modified animals with in silico and in vitro experiments to determine whether the selective activation of Stat3 in tubular cells is involved in the development of interstitial fibrosis. Nephron reduction caused Stat3 phosphorylation in tubular cells of lesion-prone mice but not in resistant mice. Furthermore, specific deletion of Stat3 in tubular cells significantly reduced the extent of interstitial fibrosis, which correlated with reduced fibroblast proliferation and matrix synthesis, after nephron reduction. Mechanistically, in vitro tubular Stat3 activation triggered the expression of a specific subset of paracrine profibrotic factors, including Lcn2, Pdgfb, and Timp1. Together, our results provide a molecular link between tubular and interstitial cells during CKD progression and identify Stat3 as a central regulator of this link and a promising therapeutic target.
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http://dx.doi.org/10.1681/ASN.2015091014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118479PMC
December 2016

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner.

Cell Signal 2016 08 16;28(8):907-16. Epub 2016 Apr 16.

Institute of Biology, Department of Systems Biology, Otto-von-Guericke University, Universitätsplatz 2, Gebäude 28, 39106 Magdeburg, Germany. Electronic address:

Interleukin 6 (IL-6) is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by IL-6 is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.
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http://dx.doi.org/10.1016/j.cellsig.2016.04.004DOI Listing
August 2016

Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression.

Nat Med 2016 05 18;22(5):497-505. Epub 2016 Apr 18.

Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, California, USA.

Fibrosis compromises pancreatic ductal carcinoma (PDAC) treatment and contributes to patient mortality, yet antistromal therapies are controversial. We found that human PDACs with impaired epithelial transforming growth factor-β (TGF-β) signaling have high epithelial STAT3 activity and develop stiff, matricellular-enriched fibrosis associated with high epithelial tension and shorter patient survival. In several KRAS-driven mouse models, both the loss of TGF-β signaling and elevated β1-integrin mechanosignaling engaged a positive feedback loop whereby STAT3 signaling promotes tumor progression by increasing matricellular fibrosis and tissue tension. In contrast, epithelial STAT3 ablation attenuated tumor progression by reducing the stromal stiffening and epithelial contractility induced by loss of TGF-β signaling. In PDAC patient biopsies, higher matricellular protein and activated STAT3 were associated with SMAD4 mutation and shorter survival. The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.
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http://dx.doi.org/10.1038/nm.4082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860133PMC
May 2016

A relaxometric method for the assessment of intestinal permeability based on the oral administration of gadolinium-based MRI contrast agents.

NMR Biomed 2016 Apr 11;29(4):475-82. Epub 2016 Feb 11.

Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.

Herein, a new relaxometric method for the assessment of intestinal permeability based on the oral administration of clinically approved gadolinium (Gd)-based MRI contrast agents (CAs) is proposed. The fast, easily performed and cheap measurement of the longitudinal water proton relaxation rate (R1) in urine reports the amount of paramagnetic probe that has escaped the gastrointestinal tract. The proposed method appears to be a compelling alternative to the available methods for the assessment of intestinal permeability. The method was tested on the murine model of dextran sulfate sodium (DSS)-induced colitis in comparison with healthy mice. Three CAs were tested, namely ProHance®, MultiHance® and Magnevist®. Urine was collected for 24 h after the oral ingestion of the Gd-containing CA at day 3-4 (severe damage stage) and day 8-9 (recovery stage) after treatment with DSS. The Gd content in urine measured by (1)H relaxometry was confirmed by inductively coupled plasma-mass spectrometry (ICP-MS). The extent of urinary excretion was given as a percentage of excreted Gd over the total ingested dose. The method was validated by comparing the results obtained with the established methodology based on the lactulose/mannitol and sucralose tests. For ProHance and Magnevist, the excreted amounts in the severe stage of damage were 2.5-3 times higher than in control mice. At the recovery stage, no significant differences were observed with respect to healthy mice. Overall, a very good correlation with the lactulose/mannitol and sucralose results was obtained. In the case of MultiHance, the percentage of excreted Gd complex was not significantly different from that of control mice in either the severe or recovery stages. The difference from ProHance and Magnevist was explained on the basis of the (known) partial biliary excretion of MultiHance in mice.
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http://dx.doi.org/10.1002/nbm.3471DOI Listing
April 2016

The apical ectodermal ridge of the mouse model of ectrodactyly Dlx5;Dlx6-/- shows altered stratification and cell polarity, which are restored by exogenous Wnt5a ligand.

Hum Mol Genet 2016 Feb 18;25(4):740-54. Epub 2015 Dec 18.

Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy,

The congenital malformation split hand/foot (SHFM) is characterized by missing central fingers and dysmorphology or fusion of the remaining ones. Type-1 SHFM is linked to deletions/rearrangements of the DLX5-DLX6 locus and point mutations in the DLX5 gene. The ectrodactyly phenotype is reproduced in mice by the double knockout (DKO) of Dlx5 and Dlx6. During limb development, the apical ectodermal ridge (AER) is a key-signaling center responsible for early proximal-distal growth and patterning. In Dlx5;6 DKO hindlimbs, the central wedge of the AER loses multilayered organization and shows down-regulation of FGF8 and Dlx2. In search for the mechanism, we examined the non-canonical Wnt signaling, considering that Dwnt-5 is a target of distalless in Drosophila and the knockout of Wnt5, Ryk, Ror2 and Vangl2 in the mouse causes severe limb malformations. We found that in Dlx5;6 DKO limbs, the AER expresses lower levels of Wnt5a, shows scattered β-catenin responsive cells and altered basolateral and planar cell polarity (PCP). The addition of Wnt5a to cultured embryonic limbs restored the expression of AER markers and its stratification. Conversely, the inhibition of the PCP molecule c-jun N-terminal kinase caused a loss of AER marker expression. In vitro, the addition of Wnt5a on mixed primary cultures of embryonic ectoderm and mesenchyme was able to confer re-polarization. We conclude that the Dlx-related ectrodactyly defect is associated with the loss of basoapical and PCP, due to reduced Wnt5a expression and that the restoration of the Wnt5a level is sufficient to partially reverts AER misorganization and dysmorphology.
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http://dx.doi.org/10.1093/hmg/ddv514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743692PMC
February 2016
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