# Esophageal Squamous Cell Cancer Initiation and Immune Landscape Remodeling

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $623,452

## Abstract

PROJECT SUMMARY/ABSTRACT
Esophageal squamous cell carcinoma (ESCC) accounts for over 80% of esophageal cancer cases and has a
poor prognosis, largely due to the absence of symptoms in the early stages. Although an early diagnosis of
ESCC may lead to better outcomes in treatment, early detection is challenging since ESCC originates from the
basal cell layer and invades the lamina propria. Therefore, understanding the biology of ESCC initiation and
developing model systems that recapitulate ESCC neoplasia is crucial. Currently, the mechanism of ESCC
initiation and immune landscape remodeling during ESCC initiation and tumorigenesis remain unclear. We have
established a genetically engineered murine esophageal organoid model system that has shown significant
potential to study ESCC initiation. Through CRISPR-based genetic manipulation of murine esophageal
organoids, we identified the key tumor suppressor genes most frequently deleted in ESCC patients and
established 32 esophageal organoid lines. Transcriptomics of the neoplastic organoids indicated a transcriptional
signature consistent with ESCC patients, and single-cell transcriptomics identified distinct cell lineage, multiple
root cells, and critical regulons of such neoplastic organoids. Interestingly, only specific neoplastic organoid-
derived cells developed tumors in immunocompetent mice. Our preliminary results suggest that the loss of tumor
suppressor genes is a crucial event for ESCC initiation by inducing esophageal neoplasia (cell-autonomous) and
remodeling the immune landscape (non-cell-autonomous). Therefore, we hypothesize that the combinatorial loss
of tumor suppressor genes initiates ESCC by inducing esophageal neoplasia, cell plasticity, and immune
evasion. This hypothesis will be tested through two specific aims: Aim 1. To determine the genetic and
transcriptional network initiating ESCC using new model systems; Aim 2. To determine the impact of targeting
the ESCC-driven immune landscape remodeling on ESCC initiation and tumorigenesis. The study will fill the
current knowledge gap by unveiling the biology of ESCC initiation and providing new models for developing
viable therapeutic applications for early ESCC.

## Key facts

- **NIH application ID:** 10799833
- **Project number:** 1R01CA278971-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jae-Il Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $623,452
- **Award type:** 1
- **Project period:** 2023-12-29 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10799833

## Citation

> US National Institutes of Health, RePORTER application 10799833, Esophageal Squamous Cell Cancer Initiation and Immune Landscape Remodeling (1R01CA278971-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10799833. Licensed CC0.

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