# Molecular mechanisms driving mesenchymal colorectal cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $457,226

## Abstract

SUMMARY
A stem-mesenchymal phenotype of the tumor epithelium, and its associated immunosuppressive and
desmoplastic stroma, are fundamental characteristics of the most aggressive and poor survival type of
colorectal cancer CRC. However, the molecular and cellular mechanisms driving this process are still far from
clear. This proposal stems from a series of recently published and unpublished observations in my laboratory
that identify the two atypical PKCs (aPKC; PKC and PKC/) as novel tumor suppressors acting in concert to
prevent this aggressive form of CRC. Thus, the simultaneous loss of both aPKCs in the intestinal epithelium (in
a new DKOIEC mouse line) results in highly mesenchymal adenocarcinomas with a reactive and strongly
immunosuppressed stroma. Both aPKCs are significantly downregulated in mesenchymal/stromal/
immunosuppressive CRC human patients who have the most unfavorable prognosis. Our unpublished
preliminary data demonstrate that intestinal epithelial cells (IECs) deficient in PKC/ (or both aPKCs)
upregulate the stem cell receptor CD44, concomitant with the downregulation of Lgr5+ intestinal stem cells,
suggesting the appearance of a new type of tumor initiating cells (TICs). Inhibition of CD44+ in tumor organoids
demonstrate its requirement for growth and supports its physiopathological relevance. Consistently, inhibition
of one of the key CD44 stromal ligands (hyaluronan) in vivo abrogates the mesenchymal phenotype of DKOIEC
tumors inhibiting the immunosuppressive response and restoring immunosurveillance. We hypothesize that the
upregulation of a new type of CD44+/Lgr5- TICs by the loss of PKC/ is central in the development of the
aggressive type of CRC. The upregulation of the MAP kinase cascades, together with the identification, in a
series of unbiassed approaches, of the transcription factor KLF4 as a potential critical intermediary between
PKC/ and CD44 expression, led us to hypothesize that the activation of ERK/JNK by PKC/ deficiency
triggers AP1 and, concurrently, induces the degradation of KLF4; both actions cooperate to drive CD44
expression and the mesenchymal phenotype of very aggressive CRC. Therefore, in this proposal, we will
determine the role of CD44 in the aggressive/mesenchymal type of CRC (Aim 1), as well as the molecular
mechanisms whereby PKC/ regulates CD44 expression and function in this process (Aim 2). The successful
completion of the proposed studies will create a new paradigm of significance and impact that will contribute to
a more comprehensive understanding of the mechanisms driving the poor prognosis mesenchymal type of
CRC, which will be key for the design of new therapeutic targets for this type of aggressive neoplasia.

## Key facts

- **NIH application ID:** 10130346
- **Project number:** 1R01CA250025-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jorge Moscat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,226
- **Award type:** 1
- **Project period:** 2021-03-17 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130346

## Citation

> US National Institutes of Health, RePORTER application 10130346, Molecular mechanisms driving mesenchymal colorectal cancer (1R01CA250025-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130346. Licensed CC0.

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