# Mechanisms of Serrated Colon Tumor Suppression

> **NIH NIH R01** · RUTGERS, THE STATE UNIV OF N.J. · 2024 · $372,875

## Abstract

A lack of knowledge about the initiating moments of tumorigenesis leaves large gaps in our ability to
detect cancer early or develop prevention strategies. Our primary objective of this competitive renewal is to
define, in vivo, the immediate consequences of oncogenic mutations in BRAF during Serrated colon cancer
formation. We will pursue these studies in colon stem cells, the presumed cell-of-origin of colon cancer.
 Work from the previous grant identified new genetic modifiers of Serrated tumorigenesis. We found that
oncogenic BRAFV600E mutations paradoxically cause stem cells to differentiate rather than form tumors.
However, when we inactivated tumor suppressor transcription factors CDX2 or SMAD4, Serrated
tumorigenesis was markedly restored. Excitingly, we found that CDX2 and SMAD4 target genes can be used
to stratify human patients for their susceptibility to Serrated tumors.
 The logical extension of these studies is to understand the molecular mechanisms that occur in stem
cells in response to BRAFV600E mutations. We will focus on the downstream transcriptional effector of BRAF,
pERK, and will leverage the genetic mouse models we created to address the following Aims:
 Our previous work found that the transcription factor CDX2 preserves mature colon identity, with fetal-
specific chromatin regions opening upon CDX2-loss. We predict that pERK takes advantage accessible
chromatin upon CDX2 loss. Aim 1 will compare the activity of pERK in wild type stem cells, and BRAFV600E or
CDX2-mutant stem cells. State-of-the-art –omics approaches will allow first-of-a-kind measurements of pERK
on stem cell chromatin, within hours after the BRAFV600E mutation is expressed from its endogenous locus. We
will measure pERK binding activity, nuclear localization, and dynamic interactions with its protein partners.
 Aim 2 will look at the downstream gene regulatory consequences of the BRAFV600E mutation in stem
cells lacking SMAD4. We previously demonstrated that SMAD4 loss predisposes mice to Serrated tumor
formation, and SMAD4 is frequently mutated in human tumors. We predict that SMAD4 works with pERK to
promote differentiation and suppress stem cell renewal. Epigenomics approaches will map pERK binding to the
genome, and ATAC-seq and RNA-seq will profile changes to chromatin and the transcriptome. Finally, Aim 3
will functionally test a model that the injury/repair cycle in the colon can create a susceptible environment for
BRAF-pERK to drive tumorigenesis, with the prediction that an altered transcriptional network is permissive to
Serrated tumor formation during the injury/repair cycle. These studies would provide important pre-clinical
models to help explain and test therapeutic strategies to suppress Serrated tumor initiation in humans.
 These studies are innovative with cutting edge -omics applications and GEMMs and significant in
exploring untested mechanisms of oncogenic pERK in stem cells. Successful completion of these studies will
have us poised...

## Key facts

- **NIH application ID:** 10862607
- **Project number:** 5R01CA190558-07
- **Recipient organization:** RUTGERS, THE STATE UNIV OF N.J.
- **Principal Investigator:** MICHAEL P. VERZI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $372,875
- **Award type:** 5
- **Project period:** 2023-06-08 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862607

## Citation

> US National Institutes of Health, RePORTER application 10862607, Mechanisms of Serrated Colon Tumor Suppression (5R01CA190558-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10862607. Licensed CC0.

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