# Sprouty: Putative Oncogene in Colorectal Cancer

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2024 · —

## Abstract

Abstract
Colorectal cancer (CRC) is the leading cause of cancer-related death in the United States. Sprouty2
(Spry2) is an endogenous suppressor of receptor tyrosine kinase (RTK)/Ras/Mitogen Activated Protein
Kinase (MAPK) signaling pathways.
The objectives of this study are:
1. To assess requirement of Spry2 in CRC mouse models.
2. To generate and analyze multi-omics data set from mouse tumors and patient organoids.
3. To assess whether differential 5mC and 5hmC hotspot loci in Spry2 may contain acquired differentially
 methylated/hydroxymethlyated CpGs that can distinguish between adenomas, adenocarcinomas, and
 adjacent control mucosa.
4. Furthermore, increased Spry2 mRNA expression and differential promoter methylation within regions
 susceptible to 5mC changes associated with Spry2 expression may correlate with worse prognosis in
 advanced rectal cancer patients undergoing preoperative chemoradiotherapy (PCRT) and surgery.
 Therefore, Spry2 expression and promoter 5mC status together could serve as prognostic epimarkers
 in advanced rectal cancer patients.
5. As Spry2 is regulated in CRC by DNA-methylation within the promoter and can therefore be modulated
 by CRISPR-dCas9 tool to affect overall Spry2 expression and tumor growth, it could be considered as
 a future treatment strategy in patients.
In previous studies, Spry2 accentuates cancer phenotype in CRC. It is hypothesized that deletion of Spry2
would suppress tumorigenesis in intestinal specific mouse models. To test this hypothesis, in Aim 1a,
Sprouty2flox/flox-Cdx2-P-Cre-ERT2, and Sprouty2flox/flox-Cdx2-P-Cre-ERT2/KrasLSL-G12D double mutant mouse
models are established and effect of Spry2 deletion on azoxymethane-induced colonic tumorigenesis is
studied. Further, Spry2 deletion in mouse models is complemented with shRNA mediated suppression of
Spry2 in Kras wild-type and KrasG12D mutant organoids established from adenomas of CRC patients (Aim
1b). Studies are extended to generate multi-omics dataset from mouse adenomas and patients’ organoids
using omics methodologies to assess signaling pathways regulated by Spry2 (Aim 1c).
Perturbing epigenetic regulation of Spry2 in patients could modify disease progression. In Aim 2a, we will
identify differentially methylated 5mC and 5hmC hotspot regions of Spry2 in CRC patients to distinguish
between adenomas, adenocarcinomas, and adjacent control mucosa. In Aim 2b, we will assess Spry2
mRNA expression and promoter methylation status in pathology collection of patients who had undergone
PCRT followed by surgery (a retrospective study) to differentiate between PCRT responders vs non-
responders by comparing disease free survival. Studies will be extended to test whether 5mC is an
epigenetic target using CRISPR-dCas9 editing in CRC. In Aim 2c, by utilizing different CRC cell lines and
immunocompromised mice, we will dissect the relationship between Spry2 methylation levels in the
promoter region with Spry2 expression and tumor growth.
The propose...

## Key facts

- **NIH application ID:** 10690901
- **Project number:** 2I01BX000824-09A2
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** SHARAD KHARE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2011-10-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690901

## Citation

> US National Institutes of Health, RePORTER application 10690901, Sprouty: Putative Oncogene in Colorectal Cancer (2I01BX000824-09A2). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690901. Licensed CC0.

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