# Initiation of Diffuse and Intestinal Non-Cardia Gastric Cancer

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $67,328

## Abstract

ABSTRACT
Gastric cancer (GC), the third leading cause of cancer death worldwide, is characterized both by
histologic and molecular criteria. The two most common forms include Diffuse GC (DGC) and
Intestinal GC (IGC). Each class of GC is associated with early inactivation of a distinct tumor
suppressor, CDH1 (encoding E-cadherin) for DGC and p53 for IGC. Beyond genetic changes,
gastric cancer development is promoted by environmental factors, specifically Helicobacter
infection and exposure to dietary nitrates. We posit that addressing two fundamental questions
in the gastric cancer field: defining the cells-of-origin and defining the distinct mediators of
progression, should be addressed together given their interconnectedness. We will evaluate the
interplay of genetic and environmental precipitants to gastric cancer using novel engineered
mouse models where we can selectively target key tumor suppressors in the gastric epithelium in
concert with relevant exposures. We will then deeply interrogate tissues with the combination of
multi-omic single cell technologies enabling dual analysis of gene expression and chromatin
accessibility in individual cells and the subsequent use of spatial transcriptomic tools allowing us
to map features of individual cell types spatially to refine the cellular origins of these altered cell
types. In concert to defining cellular origins of the two primary classes of gastric cancer, our
integrated multi-omic and spatial analyses will be evaluated to define changes in cellular
programs and candidate mediators of these altered phenotypes. In addition, we will explore how
coevolving changes in the gastric microenvironment may accompany or promote the cell’s
precancerous transformation. We will better define the interaction of environmental exposures in
gastric tumorigenesis and investigate interactions of resulting early mutations with environmental
factors, testing our hypothesis that this interaction modulates both gastric cells and
microenvironment. Utilizing our cellular and spatial profiling, we will generate a map of the
microenvironment showing the development of the disease in its spatial context, which will also
be a resource for future studies. To generalize our findings in the mouse to human, we will perform
single cell multi-ome analysis of human and mouse derived organoids and expand our existing
single cell atlas of the human GI tract. Subsequently, we will perform functional validation of
candidate mediators of progression, evaluating both features intrinsic to gastric epithelial cells
and those emerging from the microenvironment. These studies will both address longstanding
debates over origins of gastric cancers as well as define new targets to prevent cancer
development.

## Key facts

- **NIH application ID:** 11114610
- **Project number:** 3R01CA272891-03S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Silas Maniatis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $67,328
- **Award type:** 3
- **Project period:** 2022-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11114610

## Citation

> US National Institutes of Health, RePORTER application 11114610, Initiation of Diffuse and Intestinal Non-Cardia Gastric Cancer (3R01CA272891-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11114610. Licensed CC0.

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