The role of bacterial dysbiosis and its influence on pancreatic cancer cell behavior

Abstract public domain (NIH RePORTER)

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA), the most commonly diagnosed form of pancreatic cancer, is a highly lethal disease that currently ranks as the third leading cause of cancer-related deaths in the United States. Surgical resection offers the best chance for long-term survival however, almost all resected patients eventually succumb to recurrent or metastatic disease. These tumors are surrounded by a highly dense and inflammatory stroma consisting of non-cancerous cells including immune, fibroblasts, and recently identified, bacterial cells. The bacterial microbiome has emerged as an important component in the progression of many cancers including PDA. Pathogenic bacteria have been found to accompany tumor growth and a distinct tumor microbiome has been correlated to patient survival and therapy resistance. Many have reported that the presence of tumor-associated bacteria supports oncogenic progression while ablation of this bacteria reduces tumor burden. However, while these findings support the theory that these distinct tumor-associated microbial communities may promote tumorigenesis, immune suppression and therapeutic resistance, the exact mechanisms by which these occur are still unclear. To explore this, I propose interrogating the interactions between the malignant epithelium and tumor-associated bacteria, to uncover synergistic mechanisms promoting tumorigenesis. Cancer cells are known to thrive within an inflammatory tumor microenvironment however, this has not yet been studied within the context of malignant microbial dysbiosis. I have found bacteria to be closely localized to malignant epithelium in human pancreatic tumors. I hypothesize that PDA- specific bacteria promote inflammatory signaling within pancreatic epithelial cells concomitant with tumorigenesis. AIM I characterizes the direct and indirect dependence of pathogenic tumor-associated bacteria on pancreatic epithelial cell inflammatory signaling and neoplastic growth. AIM II defines mechanisms via which tumor-associated bacteria mediate cancer cell behavior within the TME. Together, these aims investigate the mechanisms via which tumor-associated bacteria promote malignant epithelial progression in vitro and within the tumor microenvironment in the preclinical model. The overarching goal of this study is to clarify the tumor-promoting mechanisms of pathogenic tumor-associated bacteria to aid in identifying new targets for therapeutic intervention in PDA.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma (PDA) is a lethal disease that is projected to become the leading cause of cancer-related death in the United States by 2030. During PDA progression, the gut and tumor microbiome changes and has been associated with an immunosuppressive, chemo-resistant tumor microenvironment. This proposal seeks to identify the microbial mechanisms supporting tumorigenesis to aid in identifying new targets for therapeutic intervention in pancreatic malignancy.