[Seminar] Cholesterol orchestrates pro-tumorigenic signaling networks in the plasma membrane by Prof. Wonhwa Cho (Liberal Arts and Sciences Science Endowed Chair, UIC Distinguished Professor and Head, Chemistry Department, University of Chicago Illinois)

Description

Title: Cholesterol orchestrates pro-tumorigenic signaling networks in the plasma membrane

Speaker: Prof. Wonhwa Cho

Liberal Arts and Sciences Science Endowed Chair, UIC Distinguished Professor and Head,

Chemistry Department, University of Chicago Illinois

Website: https://chem.uic.edu/profiles/wonhwa-cho/

Summary

Although altered cholesterol metabolism is a hallmark of cancer, the precise spatial mechanisms driving oncogenesis remain elusive. Using spatiotemporally resolved quantification, we demonstrate that metabolic reprogramming selectively elevates cholesterol at the inner leaflet of the plasma membrane (IPM) across diverse cancer types. Integrated computational, biophysical, and live-cell imaging analyses reveal that elevated IPM cholesterol triggers cryptic, stimulus-independent oncogenic signaling by directly driving the recruitment and spatial assembly of key signaling protein complexes. Systematic profiling shows that while IPM cholesterol levels are differentially upregulated across distinct cancer types, they remain strictly uniform within specific cancer subtypes. Combined proximity labeling and IPM cholesterol titration further identify distinct thresholds of IPM cholesterol that selectively tune the recruitment of specific kinases, phosphatases, and scaffolding proteins. Consequently, IPM cholesterol acts as a central rheostat, orchestrating cancer-type-specific, cellintrinsic signaling networks that enforce key malignant hallmarks, including stemness and acquired drug resistance. Crucially, these non-canonical, cholesterol-driven pathways bypass conventional therapies targeted against canonical signaling. To exploit this vulnerability, we developed lipidprotein interaction inhibitors and site-specific cholesterol depletion strategies to selectively dismantle IPM cholesterol-mediated oncogenic networks. These targeted approaches demonstrate robust in vitro and in vivo efficacy and high specificity across multiple cancer models, establishing a new therapeutic framework for precision oncology.