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

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $382,375

## Abstract

Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation
Project Summary
Colorectal cancer (CRC) is a leading cause of cancer-related deaths globally. The long-term objective of
this project is 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. However, we
provide preliminary data and rationale suggesting 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, recent evidence
from our group and others has uncovered additional oncogenic pathways activated upon APC loss that
are also necessary for initiation and maintenance of CRC. In particular, we demonstrated in the prior
funding period that the Msi family of RNA binding proteins are activated upon APC loss in a Wnt-
independent manner in both murine and human CRC models, 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, we 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. Thus, we hypothesize that loss of APC can initiate
tumorigenesis through promiscuous activation of quiescent intestinal stem cells via Wnt-
independent mechanisms. We propose that APC loss initiates a number of oncogenic pathways
independent of the canonical Wnt pathway activation (including Msi induction). We 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. We 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 the...

## Key facts

- **NIH application ID:** 9922224
- **Project number:** 5R01CA168654-09
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** CHRISTOPHER Joachim LENGNER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,375
- **Award type:** 5
- **Project period:** 2017-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922224

## Citation

> US National Institutes of Health, RePORTER application 9922224, Cell type and molecular determinants of colorectal cancer initiation downstream of APC inactivation (5R01CA168654-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9922224. Licensed CC0.

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