# Role of WNT-EGFR crosstalk by EVs and exomeres in normal colon and colon cancer

> **NIH NIH P01** · VANDERBILT UNIVERSITY · 2024 · $335,100

## Abstract

Project 3 Summary (Coffey)
The Coffey lab has identified important links between WNT and EGFR signaling in cetuximab (CTX) resistance
and intestinal crypt homeostasis. We recently reported a new mode of CTX resistance due to increased WNT
signaling mediated by miR-100/-125b. These two miRs are upregulated in extracellular vesicles (EVs) released
by CTX-resistant cells and these EVs can transfer CTX resistance. In a unique EGFR and WNT reporter mouse
model, we show that activation of WNT signaling in an EGFR-sensitized background dramatically increases both
EGFR and non-cell autonomous WNT activity. Based on these findings, we propose a model of opposing
gradients of EGFR and WNT activity in the colonic stem cell niche (SCN) that contribute to homeostasis and
disruption of the gradient is a feature of neoplastic transformation. We hypothesize that in the normal crypt niche
EVs and exomeres released by the EGFR-active and WNT-active compartments reinforce the EGFR-WNT
gradient and in CRC these nanoparticles serve to drive tumor growth and define cancer progression due to their
oncogenically altered constituents. The model also provides a framework to further examine the role of EVs and
exomeres in conferring CTX resistance, at least in part, via increased WNT signaling. To examine this model
and to determine how EVs participate in CTX resistance, with the ultimate goal of devising strategies to overcome
CTX resistance, we propose three Aims. Aim 1 is to determine the effect of EVs and exomeres isolated from
highly informative paired cell lines on EGFR and WNT activity in reporter cell lines. Aim 2 is to test the hypothesis
that these EVs and exomeres regulate normal stem cell patterning and tumor progression using our unique
EGFR and WNT reporter mouse models and their derived organoids. Aim 3 is to elucidate mechanistic
underpinnings of EV participation in resistance to EGFR blockade. This work has the potential to alter our
fundamental understanding of normal stem cell function, regulation of tumor growth and processes regulating
drug resistance.

## Key facts

- **NIH application ID:** 10759442
- **Project number:** 5P01CA229123-05
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Robert J. Coffey
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $335,100
- **Award type:** 5
- **Project period:** 2020-01-22 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10759442

## Citation

> US National Institutes of Health, RePORTER application 10759442, Role of WNT-EGFR crosstalk by EVs and exomeres in normal colon and colon cancer (5P01CA229123-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10759442. Licensed CC0.

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