# Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation

> **NIH NIH R50** · UNIVERSITY OF PENNSYLVANIA · 2020 · $104,225

## Abstract

Project Summary
Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. The long-term objective of
my research on this award will be to understand the cell-type specificity and molecular mechanisms
through which inactivation of the APC tumor suppressor drives the ontogeny of colorectal cancer. APC
is mutated in the vast majority of CRC and is broadly considered the initiating event in most of these
cancers. Because of this, there has been a large amount of research into the molecular mechanisms
through which APC functions. APC is a well-established negative regulator of the canonical Wnt
signaling pathway, and consequently a wealth of evidence exists demonstrating that constitutive Wnt
pathway activation downstream of APC loss is necessary for initiation and maintenance of CRC. Recent
data however suggests that this body of research has largely overlooked several additional important
functions of this tumor suppressor, and that such functions will represent valuable points for preventative
action and therapeutic intervention in CRC. Specifically, I have uncovered additional oncogenic pathways
activated upon APC loss that are also necessary for initiation and maintenance of CRC. In particular, I
recently published data demonstrating that the Msi family of RNA binding proteins are activated upon
APC loss in a pathway that appears to lie in parallel to and not downstream of -CATENIN. I went on to
show that Msi activity is necessary for CRC initiation and maintenance, and that Msi gain of function
alone is sufficient to transform the intestinal epithelium in a Wnt-independent manner. At the cellular
level, my colleagues and I found that Msi activity acts specifically to drive metabolic activation of
quiescent (in G0) intestinal stem cells (ISCs) resulting in cell cycle entry, proliferation, and a block in their
differentiation. In contrast, Msi activity has no discernable molecular effect on the active ISC population
driven by Wnt pathway activity and previously posited to be the cell-of-origin in CRC. Previous studies
have found that these quiescent ISCs are refractory to canonical Wnt pathway stimulation in their
dormant state. Therefore, the central hypothesis of my work in the Lengner lab moving forward is that
loss of APC can initiate tumorigenesis through promiscuous activation of quiescent intestinal
stem cells via Wnt-independent mechanisms. I propose that APC loss initiates a number of
oncogenic pathways independent of the canonical Wnt pathway activation (including Msi induction). I will
test whether APC loss can initiate CRC by driving quiescent ISCs out of G0 and into the cell cycle, thus
establishing quiescent ISCs as a cell-or-origin in colorectal cancer. I will address this hypothesis using a
combination of genomic and genetic techniques with the ultimate goal of testing whether Wnt-
independent pathways activated downstream of APC loss are viable points for therapeutic intervention in
CRC.

## Key facts

- **NIH application ID:** 9986709
- **Project number:** 5R50CA221841-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ning Li
- **Activity code:** R50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $104,225
- **Award type:** 5
- **Project period:** 2017-09-19 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986709

## Citation

> US National Institutes of Health, RePORTER application 9986709, Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation (5R50CA221841-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9986709. Licensed CC0.

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