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

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.

Grant Number: 1F31CA306283-01
NIH Institute/Center: NIH
Principal Investigator: Holly Attebury