EGFR protein condensation as a regulator of Ras activity

Objectif

The epidermal growth factor receptor (EGFR) is a key regulator of cell growth, division, and survival. Abnormal EGFR activity is implicated in many cancers, and while EGFR-targeted therapies have improved patient outcomes, acquired resistance also develops. Recent discoveries suggest that EGFR can form dynamic protein assembles “condensates” on the cell membrane—clusters of proteins comprising EGFR itself and effector molecules for downstream signaling that may profoundly affect how signals are transmitted to downstream pathways such as MAPK (Ras), a central driver of cancer cell proliferation. However, the role of these condensates in modulating signal transmission remains unknown.

This project will use a model system—giant plasma membrane vesicles (GPMVs)—which preserve the complexity of cell membranes but eliminate cellular feedback loops, enabling precise control over the signaling environment. Working with world-leading experts at UC Berkeley (Prof. Jay T. Groves) and Goethe University Frankfurt (Prof. Mike Heilemann), I will: (1) determine the EGFR condensate formation and how cancer-associated EGFR mutations affect condensate formation; (2) reveal the relationship between condensation and Ras activation, including potential Ras assembly into nanoclusters; and (3) examine how EGFR interacts and co-condenses with other receptors such as MET, a known contributor to drug resistance.

The study combines fluorescence imaging, quantitative single-molecule techniques, and biochemical reconstitution. Results will provide the first quantitative map linking EGFR condensation to Ras activation, offering fresh insights into resistance mechanisms and identifying potential new intervention points. The fellowship will also equip me with unique interdisciplinary expertise in reconstitution biophysics, single-molecule microscopy, and cancer signaling—skills that will position me to lead innovative, cross-disciplinary research at the interface of biophysics and oncology.