SOX2 dosage sustains tumor-promoting inflammation to drive disease aggressiveness by modulating the FOSL2/IL6 axis

Abstract

Background Inflammation is undoubtedly a hallmark of cancer development. Its maintenance within tumors and the consequences on disease aggressiveness are insufficiently understood. Methods Data of 27 tumor entities (about 5000 samples) were downloaded from the TCGA and GEO databases. Multi-omic analyses were performed on these and in-house data to investigate molecular determinants of tumor aggressiveness. Using molecular loss-of-function data, the mechanistic underpinnings of inflammation-induced tumor aggressiveness were addressed. Patient specimens and in vivo disease models were subsequently used to validate findings. Results There was significant association between somatic copy number alterations (sCNAs) and tumor aggressiveness. SOX2 amplification was the most important feature among novel and known aggressiveness-associated alterations. Mechanistically, SOX2 regulates a group of genes, in particular the AP1 transcription factor FOSL2, to sustain pro-inflammatory signaling pathways, such as IL6-JAK-STAT3, TNFA and IL17. FOSL2 was found overexpressed in tumor sections of specifically aggressive cancers. In consequence, prolonged inflammation induces immunosuppression and activates cytidine deamination and thus DNA damage as evidenced by related mutational signatures in aggressive tumors. The DNA damage affects tumor suppressor genes such as TP53, which is the most mutated gene in aggressive tumors compared to less aggressive ones (38% vs 14%), thereby releasing cell cycle control. These results were confirmed by analyzing tissues from various tumor types and in vivo studies. Conclusion Our data demonstrate the implication of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma

“…In vitro, Fra-2 expression is strongly triggered by hypoxia and serum deprivation in PDAC cells 26 and, once activated, Fra-2 can sustain either pro- or anti-inflammatory programs, promoting DNA damage or immune evasion, depending on the context. 27 , 28 Collectively, this converging evidence supports a critical role of Fra-2 in PDAC and, potentially, in the stress response to nutrient shortage.…”

RUNX1/NPM1/H3K4me3 complex contributes to extracellular matrix remodeling via enhancing FOSL2 transcriptional activation in glioblastoma

“…FOSL2 is known as a member of the activator protein-1 (AP-1) family, which plays important roles in multiple aspects of tumor development [ 26 ]. FOSL2 can not only maintain tumor inflammation and lead to tumor metastasis through the SOX2-FOSL2-IL6 axis but also promote M2 polarization of tumor-associated macrophages in a β-catenin-dependent manner [ 27 , 28 ]. In gliomas, FOSL2 promotes tumors’ natural evolution and bone-marrow-derived macrophage polarization through the FOSL2-ANXA1-FPR1/3 axis in response to hypoxia signaling [ 29 ].…”

Role of Fra-2 in cancer

“…In turn, Fra-2 mediates the SOX2-induced upregulation of several pro-inflammatory signaling pathways that alter the composition of the immune infiltration in the TME. In PDAC samples, prolonged inflammation significantly increases Tregs, macrophages and neutrophils, and decreases activated NK cells, eventually evolving into immunosuppression [ 110 ].…”