Targeting plasma membrane spatial dynamics to suppress aberrant Wnt signaling

SUMMARY
Dysregulation of the Wnt signaling pathway has been linked to cancer in multiple tissues. For example,
most colorectal cancer (CRC) cases (~90%) are associated with aberrant Wnt signaling, due in part to
mutations (>80%) associated with Adenomatous polyposis coli (APC), a multi-functional tumor suppressor
gene. Unfortunately, attempts to target aberrant Wnt signaling using drugs still face multiple hurdles due to
poor tumor cell targeting, negative side effects associated with required long-term treatments and a poor
understanding of the mechanisms of action. Consequently, there is an urgent need to further assess non-toxic
Wnt targeted therapeutic approaches. Therefore, this proposal seeks to develop novel membrane targeted
therapeutic approaches to abate abnormal Wnt signaling in the colon. The scientific premise that supports
the proposed research on Wnt receptor plasma membrane spatial dynamics is based on the fact that Wnt
receptors and their signaling are required for CRC development within the context of a mutant APC
background. This goal is supported by our novel discovery indicating that APC mutations causing abnormal
Wnt signaling are associated with biophysical distortions in the cell plasma membrane, thereby promoting Wnt
receptor nanoclustering and downstream signaling. We have also demonstrated that select membrane
targeted dietary bioactives (MTDBs) can restore normal plasma membrane signaling by correcting cancer-
causing biophysical distortions in the cell surface. In order to unravel the intricacies of membrane-based
cancer prevention strategies, we propose to use novel mouse, Drosophila (fruit fly) and human colon organoid
model systems to elucidate the underlying mechanisms by which MTDBs reshape the cell plasma membrane
to suppress aberrant Wnt signaling.
In Aim 1, we will further probe how mutated (oncogenic) APC perturbs cholesterol homeostasis in the
colonic crypt, thereby increasing plasma membrane order and lipid raft-dependent spatiotemporal dynamics.
In Aim 2, we will test our hypothesis that oncogenic APC-induced changes in cholesterol homeostasis alters
the spatiotemporal organization (nanoclustering) of Wnt signaling-associated receptors, thereby promoting
aberrant signaling. Aim 3 will examine the ability of MTDBs to attenuate aberrant Wnt signaling and colonic
neoplasia phenotypes associated with oncogenic APC in part by “normalizing” plasma membrane biophysical
properties.
Upon completion of our proposed work, we expect to elucidate precisely how MTDBs therapeutically
modify the cell membrane to suppress aberrant Wnt signaling and tumor formation in the colon. We propose
that our novel approach to reshape plasma membrane Wnt receptor nanoclusters is a feasible CRC prevention
or therapeutic strategy.

Grant Number: 5R01CA244359-05
NIH Institute/Center: NIH
Principal Investigator: Robert Chapkin