# Esophageal squamous cell cancer initiation and immune landscape remodeling

> **NIH NIH K99** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $128,936

## Abstract

PROJECT SUMMARY/ABSTRACT
Esophageal squamous cell carcinoma (ESCC) is a lethal cancer with a 10%-25% 5-year survival rate. Given
the importance of early detection, the initiation process of ESCC must be better defined. To study this process,
we focused on preneoplastic cells, which have the potential to progress to neoplastic cells. We
comprehensively analyzed single-cell RNA-sequencing (scRNA-seq) datasets from human ESCC and healthy
donors, as well as normal adjacent to cancer datasets, to reveal the spatial characteristics of preneoplastic
cells. We also analyzed scRNA-seq data from a mouse model of carcinogen-induced ESCC to identify features
of preneoplastic cells in a temporal context. Strikingly, molecular analysis revealed that preneoplastic cells,
though histologically normal, exhibited elevated copy number variations and reduced TP53 and CDKN2A
signaling compared to healthy normal samples in both spatial and temporal datasets. The CELF2 gene
emerged as a robust marker of preneoplastic cells across both datasets, validated by an increased presence of
CELF2+ cells in Trp53 and Cdkn2a double knockout (PC) organoids. These CELF2+ cells showed increased
plasticity, acquiring cancer stem cell features and undergoing epithelial-mesenchymal plasticity (EMP). Aim 1
is to determine the cellular reprogramming in CELF2+ cells when TP53 and CDKN2A are ablated. The
reprogrammed stemness will be validated by comparing the tumorigenicity of CELF2+ and CELF2- cells of PC
organoids. Additionally, tumorigenicity of a genetically engineered mouse model with Trp53 and Cdkn2a
deletion will be tested in the presence or absence of CELF2+ cells. Cellular reprogramming will also be
evaluated by comparing the exact cell lineage of wild-type and PC organoids and PC-derived tumors.
Employing cutting-edge genetic barcoding, we will trace the entire cellular trajectory. Cell lineage established in
Aim 1 will be the most reliable reference for preneoplastic cells and normal esophageal cells. Furthermore, cell
lineage and population analyses of PC-derived tumors will elucidate the mechanism of clonal selection during
tumorigenesis. Aim 2 will address the role of EMP-undergone CELF2+ cells in immune evasion. Although EMP
is conventionally known for its function in invasion and metastasis, its role in immune evasion is less studied.
Our preliminary experiment identified mesenchymal-CELF2+ cells in the tumor niche release chemokines and
cytokines. Aim 2 will disclose the efficiency of tumorigenicity when mesenchymal-CELF2+ cells are co-cultured
with immune-rejected cells. In addition, the candidate chemokine and cytokine genes will be manipulated in
preneoplastic cells to test our working model. Collectively, the proposed study will elucidate the cellular and
genetic mechanisms of ESCC initiation. Under the guidance of Dr. Jae-Il Park, a mentor, Dr. Ko's research
skillset, such as mouse genetics, organoids, and cancer signaling, as well as the skills of writing, teaching,...

## Key facts

- **NIH application ID:** 10983849
- **Project number:** 1K99CA286761-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Kyung Pil Ko
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,936
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10983849

## Citation

> US National Institutes of Health, RePORTER application 10983849, Esophageal squamous cell cancer initiation and immune landscape remodeling (1K99CA286761-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10983849. Licensed CC0.

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