SOX2dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating theFOSL2/IL6axis

Abstract

AbstractBackgroundInflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and subsequent consequences on disease aggressiveness is less understood.MethodsMulti-omic analyses of 27 (~ 5000 samples) entities from the TCGA, GEO and in-house data was performed to investigate the molecular determinant of tumor aggressiveness. Using molecular loss of function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness was addressed.ResultsThe data revealed a significant association between somatic copy number alterations (sCNA) and tumor aggressiveness, with amplification of the transcription factorSOX2being the most important feature among novel and known aggressiveness-associated genes such asZIC5andMYEOV.Mechanistically,SOX2regulates a group of aggressiveness-related genes including theAP1transcription factorFOSL2to sustain pro-inflammatory pathway such asIL6-JAK-STAT3, TNFAandIL17signaling pathways. Prolonged inflammation induces immunosuppression and further leads to activation of cytidine deamination and consequential DNA damage evidenced by enrichment in cytidine deamination mutational signatures in aggressive tumors.The resulting DNA damage affects tumor suppressor genes such asTP53,which was the most mutated gene in aggressive tumors compared with less aggressive tumors (38% vs 14%), thereby releasing cell cycle control. This was exemplified in Glioblastoma multiform, whereTP53andIDH1mutations are predominant.IDH1mutations were almost only seen in younger patients (>45 years, > 90%) and may explain the previously reported favorable prognosis.ConclusionTaken together, our data demonstrate the implication ofSOX2in promoting DNA damage and genome instability by sustaining inflammation viaFOSL2/IL6,resulting in tumor aggressiveness.