Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Electronic Theses and Dissertations bannerUC San Diego

The role of MUC1 in metastasis dependent on EGFR and Src

Abstract

Tumor metastasis is a complex, multi-step process initially depending on local invasion and followed by intravasation, survival in the circulation, extravasation and colonization of a distant site. Many studies have shown that EGFR and Src signaling and its cooperation with integrins are involved throughout metastasis. However, the mechanisms by which cross-talk between RTK signaling and integrins contribute to metastasis are not well-described. EGFR signaling promotes carcinoma cell metastasis that is dependent on activation of both Src kinase and integrin [alpha]v[beta]5, but little is known about the downstream effectors contributing to EGFR-mediated metastasis. Therefore, the studies in this dissertation proposed to investigate novel downstream effectors of metastasis dependent on EGFR, Src, and integrin [alpha]v[beta]5. Lead candidate effector molecules were systematically identified using an in silico strategy and validated in a well-described chick CAM model of EGF-induced tumor cell metastasis. This approach revealed a requirement for MUC1 in spontaneous metastasis to the lungs but not primary tumor formation. MUC1 contributes to the mucous barrier protecting epithelial cells from the environment and participates in intracellular signaling cascades as a substrate for EGFR and Src. Interestingly, both extracellular and intracellular domains of MUC1 have been linked to tumor progression and metastasis. Expression of mutant MUC1 constructs revealed that the cytoplasmic domain is required for EGF-induced cell migration mediated by integrin [alpha]v[beta]5 and promotes metastasis without enhancing primary tumor growth. In biochemical and cell biological approaches, EGFR signaling enhanced MUC1 cleavage, nuclear localization and transcription of genes associated with metastasis. Genetic and pharmacological strategies revealed a requirement for Src in EGF-induced MUC1 cleavage and nuclear translocation, which were associated with sponteanous metastasis in a murine orthotopic pancreatic tumor model. Therefore, the findings described in this dissertation define a critical role for MUC1 in tumor metastasis regulating by cooperative signaling between EGFR, Src, and integrin [alpha]v[beta]5

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View