# Drivers of gastric pre-neoplasia

> **NIH NIH R37** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $395,738

## Abstract

PROJECT SUMMARY / ABSTRACT
Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a
sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and
adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition
between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras
activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in
gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results
described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with
dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric
carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap
as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia
to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras
activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities
are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis.
We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic
development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras
signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms
and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and
chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the
lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess
functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and
progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine
the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development.
Consequently, our results from this proposed study would provide insights in pre-clinical information to design
therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key
factors in patients with gastric cancer.

## Key facts

- **NIH application ID:** 10212349
- **Project number:** 5R37CA244970-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Eunyoung Choi
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,738
- **Award type:** 5
- **Project period:** 2020-07-10 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212349

## Citation

> US National Institutes of Health, RePORTER application 10212349, Drivers of gastric pre-neoplasia (5R37CA244970-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10212349. Licensed CC0.

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