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

Abstract

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.

Transcriptomic Study on Human Skin Samples: Identification of Two Subclasses of Actinic Keratoses

“…Among them, MMP1, overexpressed in many cancers, was recently identified as a novel diagnostic and prognostic biomarker in head and neck SCC (NHSCC) [ 25 ]. In SCC, MMP1 is the most common upregulated marker found in previous studies [ 15 , 17 , 19 , 20 , 26 , 27 ]. Recently, Zheng et al, by comparing multiple datasets, confirmed that MMP1 may be pivotal to the transition from healthy tissue to premalignant lesions to SCC [ 28 ].…”

“…Recent transcriptomic studies highlighted that even if a uniform histological criterion is used to diagnose AKs, there is a spectrum of AKs that, on the transcriptional level, resemble normal tissue versus some that resemble SCCs [ 15 , 16 , 17 , 18 ]. However, the low number of AK samples in these studies did not allow us to distinguish AK subclasses based on their transcriptional profile.…”

“…To date, there are no AK patient cohorts available in the public databases. Previously, to increase the number of patient samples, integrative transcriptomic analyses were carried out [ 17 , 19 ]. Although these studies highlighted new pathways of, and actors in, the transformation of the SCC, they did not attempt to characterize the AK.…”

The clinical relevance of OSM in inflammatory diseases: a comprehensive review

“…In OSM-knockout mice, cSCC tumor volume was reduced by approximately 30% when compared to wild-type mice after one month, however there were still significant amounts of IL-6, IL-1b, IL-23a, CXCL1, IL-4, and IFNg present in the tumor tissue compared to normal skin (194). The most understood environmental cause of cSCC is ultraviolet (UV) radiation (197). OSM signaling has been shown to suppress UV induce apoptosis of human keratinocytes and may be crucial towards early cancer progression in vitro via an increase in cell motility through ECM remodeling (197).…”

“…The most understood environmental cause of cSCC is ultraviolet (UV) radiation (197). OSM signaling has been shown to suppress UV induce apoptosis of human keratinocytes and may be crucial towards early cancer progression in vitro via an increase in cell motility through ECM remodeling (197). This indicates that OSM may not only be crucial for cSCC progression, but also may lead to a higher incidence of squamous cell carcinoma, via repression of apoptosis in keratinocytes.…”