# Integration of early genetic alterations and inflammation in gastroesophageal premalignancy

> **NIH NIH K08** · DANA-FARBER CANCER INST · 2021 · $158,040

## Abstract

PROJECT SUMMARY
 Chronic inflammation in the gastrointestinal tract promotes the development of premalignant lesions imbued
with potential devastating consequences. Defining the precise molecular mediators that collaborate with
inflammation to endorse premalignancy will inform the design of effective prevention strategies. Genomic
annotation of premalignant gastroesophageal (GE) lesions revealed that TP53 mutations occur frequently and
predict the progression to cancer. Based on these observations, we hypothesize that chronic inflammation
provides a selective advantage for GE cells harboring TP53 mutations to generate premalignant disease. The
objective of this mentored research career development proposal is to combine our recent findings in cancer
genomics with novel mouse models of inflammation to derive new conceptual insights into the premalignant
state. To this end, we have designed an experimental system that integrates TP53 alterations in GE cells with
two modes of inflammation using a novel mouse model (Aim 1). By labeling TP53 mutant GE cells with
fluorescent probes, we will be able to track the evolution of premalignant disease in the setting of inflammation.
Furthermore, direct analysis of premalignant lesions from these studies will help elucidate specific mutations
and/or pathways that enable a selective advantage for TP53 mutant GE cells. We will also utilize an in vitro
system to systematically test the impact of disease-relevant inflammation-associated factors on cellular
functions of TP53 altered GE cells (Aim 2). Our preliminary data showed that deletion of TP53 in premalignant
GE cells stimulates the production of inflammatory cytokines, implicating a potential vicious feedback cycle.
Using a complement of mouse models, organoid culture, and patient samples, we will investigate the functional
significance of inflammation pathways induced by TP53 alterations in premalignant GE lesions (Aim 3).
Overall, these studies hold tremendous promise for cancer prevention in GE premalignancy.
 I am a medical oncologist with a research background in cellular and molecular biology. My long-term goal
is to become a tenure-track independent laboratory investigator with expertise in gastrointestinal diseases. I
am dedicated to leading a basic and translational research laboratory that defines key functional mechanisms
of premalignant gastrointestinal disease with an emphasis on inflammation, genomics, and therapeutics.
During my proposed training period, I will perform mentored research in the laboratory of Dr. Adam Bass at the
Dana-Farber Cancer Institute. I am fortunate to have an exceptional advisory committee to help guide my
research and career development including Dr. William Kaelin, Dr. Benjamin Ebert, Dr. Timothy Wang, Dr. Anil
Rustgi, and Dr. Kevin Haigis. Coupled with an outstanding institutional environment, training plan, and career
development program, the proposed research will enable me to achieve my long-term career aspiration...

## Key facts

- **NIH application ID:** 10115713
- **Project number:** 5K08DK120930-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Nilay Sethi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $158,040
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115713

## Citation

> US National Institutes of Health, RePORTER application 10115713, Integration of early genetic alterations and inflammation in gastroesophageal premalignancy (5K08DK120930-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10115713. Licensed CC0.

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