Investigating endocytosis as the mechanism driving differential ligand-induced egfr responses

The National Cancer Institute awarded Yale University one hundred thousand two hundred twenty-eight dollars on December 15, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support a project fellowship investigating how endocytosis mediates differential ligand-induced epidermal growth factor receptor (EGFR) responses in cancer cells.

The fellowship funds mechanistic research into EGFR biased signaling—the phenomenon in which seven endogenous ligands activate EGFR yet each elicits distinct signaling dynamics and cellular outcomes. Aim 1 assesses how the seven endogenous EGFR ligands, dimer-strengthening or -weakening mutations, and antibodies influence receptor internalization and downstream ERK signaling output. Aim 2 determines how EGFR abundance modulates these effects using CRISPR-engineered models, lentiviral transduction, and cell lines spanning physiologic receptor levels. Quantitative flow cytometry, multiplexed immunoblotting, and confocal microscopy integrate to map these relationships. The research targets insights that could inform strategies to selectively weaken EGFR dimers or manipulate trafficking pathways, with implications for developing next-generation targeted therapies and antibody-drug conjugates. The fellowship incorporates structured training in advanced imaging and FACS-based analysis.

Performance runs through June 30, 2029, at Yale University in Connecticut. The Cancer Research Manpower program provides biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research important to the National Cancer Program.

Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that orchestrates cellular proliferation, differentiation, and survival. Dysregulated EGFR signaling drives multiple cancers, including lung, brain, and colorectal malignancies, making this pathway a cornerstone of targeted cancer therapy. While seven endogenous ligands activate EGFR, each elicits distinct signaling dynamics and cellular outcomes - a phenomenon known as biased signaling. The mechanisms underlying this selectivity remain poorly understood, and the prevailing reliance on EGFR-overexpressing models further obscures physiologically relevant regulatory processes. This fellowship proposes a mechanistic investigation into how ligand-induced EGFR dimerization strength and receptor expression level jointly dictate receptor endocytosis and signaling fidelity. Aim 1 will assess how the seven endogenous EGFR ligands, along with dimer-strengthening or -weakening mutations and antibodies, influence receptor internalization and downstream ERK signaling output. Aim 2 will determine how EGFR abundance modulates these effects, using crispr-engineered models, lentiviral transduction, and a panel of cell lines spanning physiologic receptor levels. Quantitative flow cytometry, multiplexed immunoblotting, and confocal microscopy will be integrated to map these relationships. This research is significant because biased signaling mechanisms influence cell fate decisions and could be exploited by cancers to sustain proliferation. Insights from this work could inform strategies to selectively weaken EGFR dimers or manipulate trafficking pathways, with implications for developing next-generation targeted therapies and antibody-drug conjugates (ADCS). The fellowship incorporates a structured training plan that emphasizes technical expertise (e.g., advanced imaging, facs-based analysis, crispr gene editing), scientific communication (e.g., manuscript preparation, national conference presentations), and mentorship experience through teaching and trainee supervision. The research will take place in yale university's highly collaborative environment, leveraging the extensive resources of the lemmon laboratory, the yale cancer biology institute, and the department of pharmacology. This integrated program will provide the skills and knowledge necessary for a successful independent career in mechanistic cancer research and translational therapeutics.