# SOX9 as a key transcriptional regulator of SPEM cells in gastric carcinogenesis

> **NIH NIH F31** · VANDERBILT UNIVERSITY · 2024 · $34,312

## Abstract

PROJECT SUMMARY
Gastric cancer is currently the fourth leading cause of cancer deaths worldwide and is diagnosed in
approximately one million people per year. The most common type of gastric cancer is intestinal-type, which
develops through a series of metaplastic and dysplastic lesions of the stomach lining beginning with pyloric
metaplasia. The hallmark of pyloric metaplasia is the transdifferentiation of gastric chief cells into spasmolytic
polypeptide-expressing metaplastic (SPEM) cells. While gastric carcinogenesis is histologically well defined,
the molecular drivers of the cellular and morphological changes that occur in each of these stages have not yet
been discovered. Transcription factors are proteins that control cell fate via gene expression during
development and in adult progenitor cell differentiation. To determine if transcription factors also control cell
fate in metaplastic processes in the stomach, my lab probed for the expression of select factors in carcinogenic
gastric tissue and found a strong upregulation of the master transcription factor SOX9 in SPEM cells. To follow
up on this finding, I characterized two novel transgenic mouse models of pyloric metaplasia with Sox9 knock-
out in chief cells and found that SPEM cell formation and subsequent carcinogenesis was severely disrupted. I
hypothesize that SOX9 is necessary for chief cells to transdifferentiate into SPEM cells which are
essential for carcinogenesis. To understand the significance of SOX9 in SPEM cells and carcinogenesis, I
propose three specific aims. First, I will investigate the functional role of SOX9 by performing an in vitro
experiment using organoids from Sox9 knock-out tissues to determine if SOX9 is required for chief cells to
transdifferentiate. I will also examine whether Sox9 knock-out chief cells are able to stimulate to
transdifferentiate into SPEM cells. Second, I will perform transcriptomic profiling to identify direct downstream
genes of SOX9 to elucidate its transcriptional mechanism in SPEM cell identify and function. Finally, I will
investigate the success of microenvironment recruitment which is essential to the progression of
carcinogenesis without SOX9 upregulation in chief cells. This will elucidate a biological mechanism by which
SPEM cells drive carcinogenesis. Together, these data will provide functional and transcriptional mechanisms
of SOX9 in SPEM cells during gastric cancer development. This research will move the field forward by
uncovering the molecular mechanisms of gastric carcinogenesis and will provide potential therapeutic targets
for preventing gastric cancer development.

## Key facts

- **NIH application ID:** 10901455
- **Project number:** 1F31CA284715-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Alexis A Guenther
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,312
- **Award type:** 1
- **Project period:** 2024-04-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901455

## Citation

> US National Institutes of Health, RePORTER application 10901455, SOX9 as a key transcriptional regulator of SPEM cells in gastric carcinogenesis (1F31CA284715-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10901455. Licensed CC0.

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