Abstract 3528: Influence of obesity-associated intra-tumor microbes on exacerbating cancer severity

Abstract

Abstract Background: Despite there being a well-established connection between the gut microbiome and metabolic disease in humans, intra-tumor microbes and the mechanisms by which they regulate cell signaling, inflammation, and adipocyte growth to exacerbate disease severity in cancer patients also suffering from obesity remains largely unclear. In this study, we identified microbes to be distinctly abundant in cancer patients who are obese and correlated microbe abundance to patient survival, clinical variables, and immunological genes and pathways, in order to mechanistically explain how differential microbe abundance may influence clinical outcome. Methods: Microbial reads were aligned and extracted from raw whole-transcriptome RNA-sequencing data of cancer patient samples using Pathoscope 2.0 software. The Kruskal-Wallis test was used to correlate body mass index (BMI)-associated microbes to clinical variables. Reactome FIViz and Gene Set Enrichment Analysis were used to calculate pathway enrichment. Results: We identified specific microbes, including Pseudomonas fluorescens SBW25 and Enterobacter cloacae, and chemokine and interleukin-related genes to be potential determining factors of disease severity among cancer patients in BMI-associated groups. Gene set enrichment analysis revealed that microbes abundant in cancer tissue in obese patient samples, including Pseudomonas baetica in liver cancer patients, were significantly associated with the upregulation oncogenic, cell migration-related signaling pathways. Intra-tumor microbes from obese patient samples were also found to correlate with chemokine signaling and TFR2/NFkB-related genes, both of which have well-established roles in inflammatory activity. Conclusions: Our study significantly advances the understanding of the microbiome composition of the tumor microenvironment in patients who are obese and microbes’ relationship with clinical and immunologic variables, particularly inflammatory-related genes and pathways. We uncovered unknown mechanisms of the microbiome-immune interaction and obtained definitive data on microbiome dysbiosis in patients with obesity as a key determinant of severity of cancer, including microbe regulation of inflammasome activity. While deeper sequencing, more rigorous contamination correction, and in vitro and in vivo experiments are necessary to fully elucidate how microbe species can effectively act as therapeutic agents in probiotic and prebiotic therapies to reduce insulin resistance, inflammation, and glucose levels, our results are essential for guiding this future research. Citation Format: Aditi Gnanasekar, Neil Shende, Jaideep Chakladar, Wei T. Li, Lindsay M. Wong, Michael Karin, Weg M. Ongkeko. Influence of obesity-associated intra-tumor microbes on exacerbating cancer severity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3528.