# Role of genomic and microenvironment factors in conferring acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $346,126

## Abstract

Project 3 Summary
Esophageal cancer is the sixth most common cause of deaths worldwide with a 5-year survival rate of less than
20%. Similar to other intrathoracic malignancies, such as lung cancer, chemoradiation therapy (CRT) is an
effective tool for treating esophageal adenocarcinoma (EAC). However, CRT leads to complete responses in
EAC in only approximately 25% of patients. Thus, characterizing the cellular and molecular changes that occur
in the tumor and tumor microenvironment during CRT can provide highly accurate predictive tools to identify
which EAC patients will develop acquired resistance to therapy. CRT induces the cell death pathway ferroptosis
in cancer cells, and the hypothesis that ferroptosis is a key regulator in acquired radiation therapy resistance is
a central theme of the Acquired Resistance to Therapy and Iron (ARTI) Center. Project 3 will contribute to
this central theme by bridging the basic science mechanisms in preclinical models discovered in Project 1 and
Project 2 with clinical EAC tumor biopsies, collected at baseline (before treatment) and during the middle of the
CRT regimen. These EAC tumor biopsies will undergo single cell transcriptome profiling to identify expression
of ferroptosis-related genes and to provide an understanding of the complex communications between tumor
cells and cells of the tumor microenvironment that may drive and/or regulate ferroptosis (Aim 1). Identification
of transcriptomes that are directly or indirectly related to ferroptosis may help to prognose EAC patients who
may or may not respond to CRT. Further spatial cellular mapping and deciphering the relationship of differentially
expressed genes with ferroptosis will provide evidence for the tumor’s ability to evade ferroptosis upon
irradiation. Aim 2 will focus on determining whether adaptive resistance to therapy occurs due to selection of
rare, but pre-existing tumor cells, or due to de novo acquisition of alterations in genes directly or indirectly related
to ferroptosis signaling pathways. Aim 3 will focus on elucidating the tumor microenvironment mechanisms that
may confer ferroptosis resistance to CRT, such as fibroblasts, which have been shown to regulate the cystine
transporter SCL7A11 that promotes ferroptosis resistance. In addition, tumor-infiltrated immune cells with
hypoxic signatures will be analyzed for their association with ferroptosis resistance to CRT. In EAC tumors
resistant to CRT, myeloid cell expansion was observed, and the phenotype and activation status of myeloid cells
will be assessed using orthotopically transplanted patient derived EAC tumors. Further application of an
innovative positron emission tomography tracer from the Molecular Imaging Core of the ARTI Center to assess
oxidative potential of tumors as related to the myeloid cell expansion observed in resistant tumors will help
discover molecular and cellular pathways related to ferroptosis. Project 3 will iteratively strengthen and support
the basic ...

## Key facts

- **NIH application ID:** 10517145
- **Project number:** 1U54CA274220-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Steven Hsesheng Lin
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $346,126
- **Award type:** 1
- **Project period:** 2022-09-20 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517145

## Citation

> US National Institutes of Health, RePORTER application 10517145, Role of genomic and microenvironment factors in conferring acquired resistance to ferroptosis to chemoradiation in esophageal adenocarcinoma (1U54CA274220-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10517145. Licensed CC0.

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