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Title page for ETD etd-07212016-161343


Type of Document Dissertation
Author Sinha, Seema
URN etd-07212016-161343
Title A Novel Role of Cortactin in Exosome Secretion and Tumor Progression
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Dr. Rebecca S. Cook Committee Chair
Dr. Alissa M. Weaver Committee Member
Dr. Matthew J. Tyska Committee Member
Dr. Rebecca A. Ihrie Committee Member
Dr. Robert J. Coffey Committee Member
Keywords
  • Cancer
  • Endosomes
  • Cytoskeleton
  • Exosomes
  • Actin
  • Cortactin
Date of Defense 2016-07-15
Availability restricted
Abstract
Exosomes are extracellular vesicles that carry a variety of RNA and protein cargos, including growth factors, transmembrane proteins, angiogenic factors, proteinases, and microRNA. However, the mechanisms that regulate exosome secretion are still poorly understood. This dissertation work shows that the tumor-overexpressed cytoskeletal protein cortactin promotes exosome secretion. Knockdown or overexpression of cortactin in head and neck squamous cell carcinoma, fibrosarcoma, and breast cancer cells leads to a corresponding decrease or increase in exosome secretion. However, cortactin knockdown does not affect cargo sorting or exosome biogenesis. Rescue experiments carried out by adding purified exosomes back to cortactin-knockdown cells suggest that exosome secretion may account for many functions of cortactin in tumor aggressiveness. Furthermore, live imaging revealed that cortactin controls both trafficking and plasma membrane docking of multivesicular endosomes. Mechanistically, interaction of cortactin with Arp2/3 complex and branched actin is critical for exosome secretion. Also, cortactin, Rab27a, and coronin 1b coordinately control stability of cortical actin multivesicular endosome docking sites along with exosome secretion. Overall, this dissertation identifies molecular and cellular mechanisms important for exosome secretion.
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