Oncostatin M is overexpressed in skin squamous-cell carcinoma and promotes tumor progression

Simonneau, Marie; Frouin, Éric; Huguier, V.; Jermidi, Cynthia; Jégou, Jean‐François; Godet, Julie; Barra, Anne; Pâris, Isabelle; Levillain, P.; Cordier-Dirikoc, Sevda; Pedretti, Nathalie; Bernard, François; Lecron, Jean‐Claude; Morel, Franck; Favot, Laure

doi:10.18632/oncotarget.26355

Cited by 21 publications

(24 citation statements)

References 58 publications

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“…These initial data prompted us to characterize OSM involvement in keratinocytes. Here, OSM-enhanced motility is in accordance with previous in vitro studies 42,45,46 . Such tumor-promoting effects were regulated through JAK/STAT3 pathways 44,46 .…”

Section: Discussionsupporting

confidence: 92%

“…OSM has been reported to promote a variety of pathologies, including skin inflammation, and various types of squamous cell carcinoma 35 , 36 , 42 – 44 . Integrated analyses using multiple data sets and pathway analysis platforms suggested that Oncostatin M signaling was activated early in UV-exposed skin and wounded skin as well as in cuSCC tumors (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development

Nguyen¹,

Rajapakshe²,

Nicholas³

et al. 2020

Sci Rep

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Cutaneous squamous cell carcinoma (cuSCC) is the second most common skin cancer and commonly arises in chronically UV-exposed skin or chronic wounds. Since UV exposure and chronic wounds are the two most prominent environmental factors that lead to cuSCC initiation, we undertook this study to test whether more acute molecular responses to UV and wounding overlapped with molecular signatures of cuSCC. We reasoned that transcriptional signatures in common between acutely UV-exposed skin, wounded skin, and cuSCC tumors, might enable us to identify important pathways contributing to cuSCC. We performed transcriptomic analysis on acutely UV-exposed human skin and integrated those findings with datasets from wounded skin and our transcriptomic data on cuSCC using functional pair analysis, GSEA, and pathway analysis. Integrated analyses revealed significant overlap between these three datasets, thus highlighting deep molecular similarities these biological processes, and we identified Oncostatin M (OSM) as a potential common upstream driver. Expression of OSM and its downstream targets correlated with poorer overall survival in head and neck SCC patients. In vitro, OSM promoted invasiveness of keratinocytes and cuSCC cells and suppressed apoptosis of irradiated keratinocytes. Together, these results support the concept of using an integrated, biologically-informed approach to identify potential promoters of tumorigenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development

Nguyen¹,

Rajapakshe²,

Nicholas³

et al. 2020

Sci Rep

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“…During inflammation, neutrophils are among the first phagocytes to infiltrate the tissue, mostly through CXC chemokine-mediated chemotaxis, and these cells predominate in the SCC invasive front ( Kruger et al, 2015 ; Simonneau et al, 2018 ; Khou et al, 2020 ). Progressive infiltration of tumor-associated neutrophils (TANs) was observed during the evolution of benign papillomas to established SCC lesions in a chemical carcinogenesis model, and tumor escape mostly involved the impairment of anti-tumor CD8 + T cell responses mediated by high arginase activity, production of reactive oxygen species (ROS), nitrite (NO), and the induction of PD-1 expression on CD8 + T cells ( Khou et al, 2020 ; Figure 1C ).…”

Section: Cellular Composition Of the Tumor Microenvironmentmentioning

confidence: 99%

“…The authors also demonstrated that hypoxia is crucial for N2 phenotype maintenance and tumor oxygenation can revert TANs phenotype toward N1 ( Mahiddine et al, 2020 ). Tumor-associated macrophages (TAMs) also represent a significant percentage of infiltrating phagocyte population in SCC ( Kambayashi et al, 2013 ; Amôr et al, 2018 ; Simonneau et al, 2018 ; Jiang et al, 2019 ), and specific depletion of these cells inhibited tumor growth ( Takahashi et al, 2009 ). The recruitment of monocytes into the SCC is mediated by CC chemokines such as CCL2 and, once in the TME, monocyte-derived macrophages are polarized toward a M1 or M2 phenotype ( Pettersen et al, 2011 ; Caley et al, 2020 ).…”

Section: Cellular Composition Of the Tumor Microenvironmentmentioning

confidence: 99%

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Amôr

Santos

Campanelli

2021

Front. Cell Dev. Biol.

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Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

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“…A member of the IL6 family, it is an important inflammatory mediator in the skin ( Boniface et al, 2007 ) and is known to suppress differentiation in cooperation with other cytokines ( Rabeony et al, 2014 ). It also promotes proliferation of certain tumor cell types and progression of cutaneous and squamous cell carcinomas ( Simonneau et al, 2018 ). Like other cytokines, OSM signals through STAT1 and STAT3 as well as the mitogen-activated protein kinase pathway ( Dey et al, 2013 ), where sustained phosphorylation on tyrosine residues helps maintain transcriptional activity ( Andrés et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown

Hong

Lee

Rice

2020

PeerJ

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Cytokine signaling in the epidermis has an important role in maintaining barrier function and is perturbed in pathological conditions. Environmental exposures, such as to metal compounds, are of interest for their potential contribution to skin disease. Present work explores the possibility that vanadate is a more effective protein tyrosine phosphatase inhibitor in human keratinocytes than previously observed in fibroblasts. It focuses on the state of phosphorylation of signal transducer and activator of transcription 1 (STAT1) on tyrosine 701 upon treatment of cultured human keratinocytes with the cytokine oncostatin M, a cutaneous inflammatory mediator that is highly effective in suppressing several differentiation markers and in preserving proliferative potential of keratinocytes. Exposure to sodium vanadate in the medium greatly prolonged the phosphorylation of STAT1, but only at high concentration (>30 µM). Inhibitors of protein tyrosine phosphatases known to dephosphorylate STAT1 (SHP2, TCPTP, PTP1B) were ineffective in mimicking the action of vanadate. The irreversible protein tyrosine phosphatase inhibitor phenyl vinyl sulfonate alone induced STAT1 phosphorylation and appeared to induce its limited cleavage. It also inhibited cross-linked envelope formation, a characteristic step of keratinocyte terminal differentiation, likely due to its reaction with the active site cysteine of keratinocyte transglutaminase. Thus, the key protein tyrosine phosphatase responsible for STAT1 dephosphorylation remains to be identified, and an off-target effect of a potential inhibitor was revealed.

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Oncostatin M is overexpressed in skin squamous-cell carcinoma and promotes tumor progression

Cited by 21 publications

References 58 publications

Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development

Integrative transcriptomic analysis for linking acute stress responses to squamous cell carcinoma development

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Off-target effects of protein tyrosine phosphatase inhibitors on oncostatin M-treated human epidermal keratinocytes: the phosphatase targeting STAT1 remains unknown

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