Fig. 2

SOX2 promotes disease aggressiveness by enhancing inflammatory and oncogenic signaling via FOSL2. (A; left panel) A bar plot showing enriched hallmark gene sets in poor and better outcome cancers. Gene sets are considered to be enriched, if the show a false discovery rate of < 0.05. (A; right panel) Representative enrichment plot for pro-inflammatory hallmarks gene sets that are enriched in poor outcome cancers. (B) Boxplots showing the 10 most enriched gene from the hallmarks of TNFA signaling via NFKB. The hallmarks of TNFA signaling via NFKB was the most significantly enriched hallmark gene set in poor outcome cancers. (C) A heatmap showing the expression of significantly differentially expressed transcription factors upon SOX2 knockdown. (D; (left panel) SOX2 ChIP-sep peak profile showing enrichment around the FOSL2 gene (upper left panel) and FOSL2 ChIP-seq peaks around the IL6 gene (lower left panel) (IL6-JAK-STAT3 signaling is one of the top enriched hallmark gene sets in poor outcome cancers). (D; right panel) A pathway plot showing significantly enriched pathways in SOX2 ChIP-seq data. The ChIP-seq data was derived from the wildtype of the prostate cancer cell lines CWR-R1 and WA01. (E; left panel) A Venn diagram showing the intersection between upregulated and downregulated genes in poor out come and better outcome samples and between FOSL2^high and FOSL2^low samples. (E; right panel) A heatmap comparing enriched hallmark pathways in poor and better outcome cancers and FOSL2^high and FOSL2^low samples. FOSL2^high and FOSL2^low samples are samples with less than 1000 copies or more than 10,000 copies, respectively. This approach was used investigate if high expression of FOSL2 is related to the enriched hallmark gene sets seen in the poor outcome cancers. (F) FOSL2 staining of PAAD xenografts for fast and slow growing tumors (left panel) and tumor growth curves for the corresponding tumors (right panel). (G; left panel) Boxplots showing the expression of the proinflammatory cytokine IL6 and its downstream effector STAT3 in FOSL2 high and low tumors. FOSL2 high and low groups are the same as described above. (G; middle panel) Expression of FOSL2 and the proinflammatory mediator STAT3 in different compartments of PAAD tumors. Data is derived from laser microdissected (Maurer et al., 2019) PAAD tumors. The expression of IL6 was very low in majority of the cases and is not presented. (G; right panel) IL6 gene expression in grade II and grade III PAAD tumors (left panel) and in Qm and classical PAAD subtypes (right panel). Data was generated from resected PAAD samples. (H; left panel) Expression of inflammatory mediators and tumor microenvironment marker genes in normal pancreas (n = 41), chronic pancreatitis tissue (n = 59) and PAAD tissues n = 195). (H; right panel) Immune cell proportions derived from deconvolution of gene expression data from normal pancreas tissue, chronic pancreatitis tissue and PAAD tissue. Immune cell proportions were determined with CIBERSORT as implemented in TIMER. (I) Boxplots showing immune cell proportions in poor outcome vs better outcome cancers. (J) Top five mutational signatures in cancer entities with better outcome (upper panel) and poor outcome (lower panel). (K) Top ten most mutated genes in poor outcome cancers (left panel) and better outcome cancers (right panel)