# EPHB2-Dependent Signaling: A New Molecular Paradigm in Barrett's Neoplasia

> **NIH NIH P01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $387,708

## Abstract

PROJECT SUMMARY/ABSTRACT
The etiology of Barrett's esophagus (BE), a molecularly complex disorder of the distal esophagus, remains
elusive. Patients with BE are at an increased risk of developing esophageal adenocarcinoma (EAC), a lethal,
increasingly prevalent, and the most common esophageal malignancy in the U.S. Our long-term objective is to
identify the causative mechanisms underlying the onset and malignant progression of BE, and to develop
evidence-based biomarkers and chemopreventive/therapeutic strategies for subsequent clinical implementation.
Project 3 of this program is based on our recent discovery of EphB2 Receptor Tyrosine Kinase as a novel
promoter of Barrett's neoplasia. RNA sequencing coupled with pathway modeling in treatment-naïve patient
biopsies showed significant hyperactivation of EphB2 signaling in the vast majority (>90%) of BE and EAC
lesions. Phenotypic assessments in vitro and in vivo demonstrated EphB2 signaling to be essential for the
viability of EAC and dysplastic/BE cells. Subsequent mechanistic studies identified c-MYC as a novel target of
EphB2 signaling, while single-cell RNA sequencing of esophageal progenitor cells further confirmed a strong
association of EphB2 activation with columnar/BE-like cell lineage. Collectively, our study implicates EphB2
signaling for the first time in BE-EAC pathogenesis, and further reveals a novel link between EphB2 and MYC in
any disease context. Expanding on these provocative findings, we now propose to fully characterize the biologic
role of EphB2 in Barrett's neoplasia as follows: In Aim 1, we will determine whether EphB2 activation is a
consequence of, or a pre-requisite for, columnar/BE metaplasia development. We will test whether activation of
EphB2 signaling in putative BE-progenitor cells promote columnar/BE-like transformative state. In Aim 2, we will
determine the pathologic consequences of EphB2 activation in vivo in the esophagus, using a constitutively-
active EphB2 kinase (Ephb2F613D) mouse model that we recently developed. We will specifically test if EphB2
activation induces BE-like metaplasia and dysplasia/cancer in the esophagus; either spontaneously, or upon
exposure to reflux injury, and/or in the setting of esophageal inflammation. We will further characterize the key
molecular programs disrupted by EphB2 activation in the esophagus. In Aim 3, we will determine the downstream
and upstream regulatory cascades of EphB2 signaling. Collectively, our proposed studies will delineate the role
of EphB2 signaling for the first time, uncovering novel driver mechanisms of BE-EAC pathogenesis.

## Key facts

- **NIH application ID:** 10932163
- **Project number:** 5P01CA269019-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Andrew Edward Blum
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $387,708
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932163

## Citation

> US National Institutes of Health, RePORTER application 10932163, EPHB2-Dependent Signaling: A New Molecular Paradigm in Barrett's Neoplasia (5P01CA269019-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10932163. Licensed CC0.

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