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Title page for ETD etd-12202017-111207


Type of Document Dissertation
Author Erdogan, Begum
Author's Email Address erdoganbeg@gmail.com
URN etd-12202017-111207
Title Increased traction forces by cancer-associated fibroblasts align fibronectin to direct cancer cell migration
Degree PhD
Department Biological Sciences
Advisory Committee
Advisor Name Title
Dr. Todd R. Graham Committee Chair
Dr. Alissa M. Weaver Committee Member
Dr. Charles K. Singleton Committee Member
Dr. Deyu Li Committee Member
Dr. Katherine L. Friedman Committee Member
Keywords
  • prostate cancer
  • integrins
  • fibronectin
  • extracellular matrix
  • Cell migration
  • cancer-associated fibroblasts
  • tumor microenvironment
Date of Defense 2017-12-15
Availability restricted
Abstract
Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin assembled by CAFs mediates CAF-cancer cell association and directional migration. Compared to normal fibroblasts (NFs), CAFs produce a fibronectin (Fn)-rich extracellular matrix (ECM) with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing MyoII- and PDGFRa-mediated contractility and traction forces which are transduced to Fn through a5b1 integrin. We further show that prostate cancer cells use av integrin to migrate efficiently and directionally on CAF-derived matrices. We also demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.
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