The Role of Secondary Bile Acids in Gastro-Esophageal Neoplasia

PROJECT SUMMARY
Stem and progenitor cells at the gastroesophageal junction (GEJ) have been identified as crucial to the
development of adenocarcinoma of the distal esophagus, gastroesophageal junction, and proximal stomach.
Combined, these cancers have over 20,000 new cases per year in the U.S., are associated high mortality, and
represent a major public health burden. Our group has identified both gastric cardia as well as GEJ transitional
basal stem cells as likely cells of origin for precancerous states in this region. However, defining the mechanisms
and effectors that drive GE junction stem cell fate and promote cancer development remains a critical gap in
knowledge. Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) represent the prototype for
neoplasia arising from GE junction stem cells. We have extensive preliminary data demonstrating that circulating
secondary bile acids derived from gut bacteria directly promote the development of BE and EAC, treating our
L2-IL1B mouse model of BE/EAC with deoxycholic acid (DCA) accelerates neoplasia, and treatment with
obeticholic acid, an agonist of nuclear bile acid receptor FXR (farnesoid X receptor), decreases proliferation,
GEJ stem cell numbers, and dysplasia. However, the exact mechanisms by which secondary bile acids impact
GEJ stem cells and the associated microenvironment have not been elucidated. We hypothesize that circulating
secondary bile acids produced by gut bacteria promote early cancer development via direct effects on GE
junction stem cells through FXR antagonism and by inducing pro-inflammatory microenvironment alterations.
Using highly novel techniques and approaches (including scRNA-Seq and CyTOF), we will perform a series of
experiments using mouse models, mouse and human organoids, and with validation of findings in a prospective
study of patients, to address the following specific aims: Aim 1. To determine the role of circulating secondary
bile acids in GEJ epithelial stem cell fate and early cancer promotion; Aim 2. To assess the effects of circulating
secondary bile acids on the GEJ epithelial stem cell microenvironment; Aim 3. To determine whether targeted
microbiome modification that regulates the circulating bile acid pool modifies GEJ cancer development. To
achieve these aims we will use our unique L2-IL1B mouse model with FXR knockout in stem cells (L2-
IL1B/Fxrfl/fl), allowing us to assess the effects of secondary bile acids on GEJ stem cells as well the L2-IL1B/Nlrpfl/fl
model to explore inflammasome activation in stem cells and assess for cross-talk with the microenvironment.
Ultimately, we will perform experiments treating with distinct consortia of highly characterized bacterial strains
to modulate the secondary bile acid producing capacity of the gut microbiome and determine the effects on
cancers arising from GE junction stem cells. Elucidation of the specific mechanisms by which secondary bile
acids interact with GEJ stem cells and modify the microenvironment to promote cancer development may lead
to the identification of novel therapeutic targets, including the potential for rationally designed probiotic therapy,
which would have a major public health impact.

Grant Number: 3R01CA272898-04S1
NIH Institute/Center: NIH
Principal Investigator: Julian Abrams