# Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2022 · $949,184

## Abstract

SUMMARY
Despite their emergence from distal esophagus and distal stomach, respectively, esophageal adenocarcinoma
(EAC) and intestinal gastric cancer (iGC) share the natural histories and molecule genetics of a single disease.
Historically, EAC and iGC were among the first cancers to be linked to the prior presence of discrete, pre-
cancerous lesions that can progress to dysplasia and then invasive disease over a two-decade interval. In
both cases the earliest precancerous lesion was an odd "intestinal metaplasia; IM" known as "Barrett's
esophagus (BE)" for EAC and "gastric intestinal metaplasia (GIM)" for iGC. These common evolutionary
features have been extended by cancer genetics breakthroughs that place EAC and iGC into single cluster
distinct from other gastric and esophageal cancers. While it was widely anticipated that advances in
endoscopic and ablative technologies applied to precursor lesions would spell the end of EAC and iGC, rates
of EAC and iGC have not appreciably decreased and most patients still present with advanced disease and
poor five-year survival. This dire clinical reality has predicated a broad effort to understand the cell-of-origin of
these diseases, their earliest emergence towards pathology, as well as their detection and pharmaceutical
elimination. A highly collaborative team consisting of upper gastrointestinal oncologists, stem cell and
molecular biologists, experts in murine cancer modeling, and proteomics specialists has employed advanced
stem cell cloning technologies to capture patient-matched stem cells in each of the successive lesions in
patients with EAC and iGC. In addition to the high-resolution phylogenetics afforded by these stem cells, this
analysis has revealed the BE and GIM stem cells are indistinguishable at the level of whole genome
expression profiling down to the level of homeotic transcription factors that define cellular identity. Common
cell surface markers of BE and GIM stem cells identify a discrete population of cells at both the
gastroesophageal (GE) junction and in the distal stomach of normal mice which we hypothesize are the
intrinsic source of the IM for EAC and iGC respectively. These markers have also enabled the cloning of the
corresponding site-specific stem cells, which we find to be indistinguishable gene expression profiles and to be
committed to IM upon in vitro differentiation. In three aims, we will 1) use similar methods to clone the intrinsic
IM stem cells from human fetal and adult GE junctions and gastric mucosa; 2) engineer mouse models for
conditional expression of oncogenic factors in intrinsic IM cells; and 3) identify small molecules that selectively
target intrinsic IM stem cells as leads for therapeutics to prevent EAC and iGC. We anticipate that the studies
proposed herein will provide new insights into the biology and origin of these remarkably similar and
widespread cancers, provide datasets essential for prospective early detection screens, and yield highly
se...

## Key facts

- **NIH application ID:** 10506192
- **Project number:** 1R01CA272906-01
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Jaffer A. Ajani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $949,184
- **Award type:** 1
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10506192

## Citation

> US National Institutes of Health, RePORTER application 10506192, Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma (1R01CA272906-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10506192. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*