# The role of stem cells and the microenvironment in gastrointestinal cancers

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $937,650

## Abstract

SUMMARY/ABSTRACT
Timothy C. Wang, NCI R35
Gastrointestinal (GI) cancers most often arise in the setting of chronic inflammation and thus the early evolution
of tumors involves extended epithelial interactions with inflammatory stroma. The Wang laboratory has focused
for decades on preneoplastic conditions such as gastritis, esophagitis, colitis and pancreatitis, and the impact of
stromal changes on epithelial progenitors. Recent work from the lab has characterized the origins of GI cancers
from resident stem and progenitor cells, which are expanded during carcinogenesis as a persistent regenerative
response, due in part to a shift from asymmetric to symmetric stem cell division. Our lab has used a combination
of genetic lineage tracing, 3D organoid models, and single cell RNA-sequencing combined with cutting edge
bioinformatic analyses to investigate normal stem and progenitor cells and their early transition to cancer cells.
This work has led to a major paradigm shift in our understanding, for example, of the origins of esophageal
adenocarcinoma. While the lab has elucidated the role of various stromal cell types, a major focus has been on
the role of nerves in modulating both epithelial progenitors as well as other stromal cells. The peripheral nervous
system includes sympathetic, parasympathetic, and sensory nerves, and our lab has pioneered the study of
these nerves in the development of GI cancers. Recent preliminary data from the laboratory has shown that
sensory nerves when activated induce rapid calcium fluxes and modulate the electrical state of tumors cells. In
addition, the laboratory has been studying the role of immature myeloid cells (IMC) that in the setting of cancer
suppress tumor immunity (i.e., MDSC), and which are also modulated by neural signaling. Previous studies have
shown that the trefoil factor TFF2, induced by the inflammatory reflex, modulates IMC and prevents the
development and expansion of MDSC which suppress CD8+ T cells in our models. In addition, we have recently
been studying the impact of myeloid cells on epigenetic changes in epithelial progenitors. Our work has led to
clinical trials and numerous collaborations which we are now seeking to expand, and broaden the impact,
particularly in the areas of nerves and cancer. Our proposed studies have the goal of better understanding the
crosstalk between nerves, myeloid cells and stem cells that lead to cancer, in order to identify new targets and
develop new, more effective and targeted therapies.

## Key facts

- **NIH application ID:** 10906176
- **Project number:** 5R35CA210088-09
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Timothy Cragin Wang
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $937,650
- **Award type:** 5
- **Project period:** 2016-01-07 → 2030-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906176

## Citation

> US National Institutes of Health, RePORTER application 10906176, The role of stem cells and the microenvironment in gastrointestinal cancers (5R35CA210088-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906176. Licensed CC0.

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