R01CA255298

The role of the metaplastic microenvironment in Barrett's esophagus - project summary

Esophageal cancer is a leading cause of cancer death worldwide. The two subtypes include esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). In the United States (US) and Western Europe, EAC is the more common subtype. In the US this year over 16,000 individuals are expected to die from EAC.

To improve survival, identification of its precursor lesion, Barrett’s esophagus is important. Barrett’s esophagus, i.e. intestinal metaplasia of the esophagus, occurs in the setting of chronic gastroesophageal reflux (GERD) when the normal stratified squamous epithelium of the esophagus is replaced by an intestinal type. Early identification of this lesion leads to regular surveillance to monitor for progression to dysplasia and adenocarcinoma. Some patients, however, never progress to EAC while others do.

Recently, in our lab we have identified that infiltrating fibroblasts and other immune cells play an important role in promoting tumorigenesis. The role and phenotype of infiltrating fibroblasts and other immune cells in promoting progression from metaplasia to dysplasia is unclear. In this proposal, we seek to clarify the role of the metaplastic microenvironment in promoting this progression to dysplasia and adenocarcinoma.

In particular, we seek to understand how activated fibroblasts interact with the esophageal microbiome and deoxycholic acid in the gastro-esophageal refluxate. We hypothesize that specific, activated fibroblasts secrete pro-tumorigenic cytokines promoting progression to dysplasia in the context of deoxycholic acid and altered esophageal microbiome induced by injury from gastro-esophageal refluxate.

This hypothesis will be pursued through the following inter-related specific aims:

1.) To assess the effect of DCA on Barrett’s esophagus associated fibroblasts.

2.) To assess the effect of Enterobacteriaceae on Barrett’s esophagus associated fibroblasts.

The parent grant addresses the hypothesis that deoxycholic acid (DCA) in gastro-esophageal refluxate induces Notch signaling in BE, decreasing goblet cell differentiation and mucus production. This in turn increases the interaction of pro-carcinogenic bacteria with the underlying epithelium, promoting the development of EAC. However, the parent R01 does not address the relationship between DCA, Notch signaling, and the microbiome with the BE-associated microenvironment. This proposal addresses this critical gap.

The Trustees Of Columbia University In The City Of New York

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

New York, New York 10032 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the End Date has been shortened from 12/31/25 to 12/31/24 and the total obligations have increased 483% from $525,287 to $3,061,711.