Lueong, S. S. | Search bioRxiv

bioRxiv2022

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

BackgroundInflammation 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 factor SOX2 being the most important feature among novel and known aggressiveness-associated genes such as ZIC5 and MYEOV. Mechanistically, SOX2 regulates a group of aggressiveness-related genes including the AP1 transcription factor FOSL2 to sustain pro-inflammatory pathway such as IL6-JAK-STAT3, TNFA and IL17 signaling 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 as TP53, 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, where TP53 and IDH1 mutations are predominant. IDH1 mutations 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 of SOX2 in promoting DNA damage and genome instability by sustaining inflammation via FOSL2/IL6, resulting in tumor aggressiveness.

cancer biology↗

bioRxiv2021

Functional metabolic phenotyping of human pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDAC) lacks targeted treatment options. Although subtypes with transcriptome-based distinct lineage and differentiation features have been identified, deduced clinically actionable targets remain elusive. We here investigate functional metabolic features of the classical and QM (quasi-mesenchymal)/basal-like PDAC subtypes potentially exploitable for non-invasive subtype differentiation and therapeutic intervention. A collection of human PDAC cell lines, primary patient derived cells (PDC), patient derived xenografts (PDX) and patient PDAC samples were transcriptionally stratified into the classical and QM subtype. Functional metabolic analyses including targeted and non-targeted metabolite profiling (matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI)), seahorse metabolic flux assays and metabolic drug targeting were performed. Hyperpolarized 13C-magnetic resonance spectroscopy (HP-MRS) of PDAC xenografts was used for in vivo detection of intra-tumoral [1-13C]pyruvate and [1-13C]lactate metabolism. We identified glycolysis and lipid metabolism/fatty acid oxidation as transcriptionally preserved metabolic pathways in QM and classical PDAC subtype respectively. However, these metabolic cues were not unambiguously functionally linked to one subtype. Striking functional metabolic heterogeneity was observed especially in primary patient derived cells with only individual samples representing high dependence on glycolysis or mitochondrial oxidation. Of note, QM cells actively use the glycolytic product lactate as oxidative mitochondrial fuel. Using HP-MRS, we were able to non-invasively differentiate glycolytic tumor xenografts with high intratumoral [1-13C]pyruvate to [1-13C]lactate conversion in vivo. Although PDAC transcriptomes indicate molecular subtype-associated distinct metabolic pathways, we found substantial functional metabolic heterogeneity independent of the molecular subtype. Non-invasive identification of highly glycolytic tumors by [1-13C]pyruvate/lactate HP-MRS support individualized metabolic targeting approaches.

cancer biology↗