# Cell Fate Regulation in Esophageal Progenitor Cells

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $563,447

## Abstract

Project Summary
Barrett’s esophagus and small cell carcinoma in the esophagus are characterized by the loss of squamous cell
identity while gaining other cell fates. Thus far effective treatment options for these diseases are limited in part
due to an incomplete understanding of the molecular mechanisms driving the initial cell fate changes. This
application will address how the transcription factor p63 directs the squamous differentiation program and safeguards
esophageal basal progenitor cells from neuroendocrine cell commitment.
We and others have demonstrated that loss of p63 leads to the abrogation of the stratified squamous epithelium
in the developing esophagus. However, how p63 regulates cell fate determination of esophageal progenitor cells
remains largely unknown. Surprisingly, we found that p63 deletion results in extensive neuroendocrine
differentiation in the esophagus. Moreover, loss of p63 expression was also observed in small cell carcinoma of
the esophagus. Inhibition of the key epigenetic silencing factor EZH2 re-activates p63 expression in
neuroendocrine cells, which is accompanied by the acquisition of squamous cell fate. We therefore hypothesize
that epigenetically regulated p63 expression suppresses neuroendocrine while promoting the squamous cell
differentiation program in the esophagus. Three specific aims are formulated to test the hypothesis. Aim 1 will
test whether the role played by p63 in cell fate determination is isoform-specific and conserved in human
esophageal progenitor cells (EPCs). We will combine mouse genetic models and human pluripotent stem cell
differentiation to address this Aim. Aim 2 will determine p63-mediated transcriptional program during the
specification of EPCs. We will use multiple epigenomic assays including ChIP-seq and ATAC-seq to determine
p63 downstream targets at the genome-wide level. We will also use biochemistry assays to test candidate genes
implicated in cell fate transition that are potentially bound and functionally regulated by p63. Aim 3 will determine
the mechanism and impact of p63 silencing on neuroendocrine commitment. In this Aim we will investigate how
p63 expression is modulated by epigenetic regulatory mechanisms during aberrant cell fate commitment, thus
identifying strategies to restore the squamous differentiation program. Combining our joint expertise on mouse
genetics, cell biology, chromatin biology and epigenomics, this work will provide novel mechanistic insights into
esophageal cell fate regulation and offer new approaches to treat neuroendocrine lesions.

## Key facts

- **NIH application ID:** 10818566
- **Project number:** 5R01DK132251-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chao Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $563,447
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818566

## Citation

> US National Institutes of Health, RePORTER application 10818566, Cell Fate Regulation in Esophageal Progenitor Cells (5R01DK132251-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10818566. Licensed CC0.

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