Elucidating cell death mechanisms in extracellular matrix-detached epithelial cells

Doctoral Dissertation
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Abstract

When mammary epithelial cells become detached from the extracellular matrix (ECM), they undergo programmed cell death. Over the past twenty years, our knowledge regarding various mechanisms utilized by cancerous epithelial cells to overcome ECM-detachment-induced death has grown. Elucidating the ways in which cancer cells overcome ECM-detachment-induced cell death is important for our understanding of the metastatic progression and for our ability to therapeutically eliminate these cells. Here, we describe a novel mechanism utilized by inflammatory breast cancer (IBC) cells to overcome ECM-detachment-induced apoptosis, or anoikis. IBC cells were shown to survive in ECM-detached conditions by regulating the intracellular localization of the proapoptotic protein, Bim-EL via protein interactions with Beclin-1 and LC8. These data are the first to describe how IBC cells can survive in an ECM-detached state.

Interestingly, inhibition of anoikis alone is not enough to overcome ECM-detachment-induced cell death in nontumorigenic mammary epithelial cells. We have identified Rip1 as a critical mediator of non-apoptotic ECM-detachment-induced cell death, which we believe to be programmed necrosis. Rip1 was found to be highly expressed in ECM-detached epithelial cells via upregulation of the deubiquitinase, CYLD. Surprisingly, Rip3 and MLKL were found to be dispensable downstream of Rip1 for ECM-detachment-induced programmed necrosis. Furthermore, TNF╬▒ does not appear to represent the stimulation factor for ECM-detachment-induced death. Together these data suggest a novel Rip1-mediated, Rip3/MLKL-independent signaling cascade for ECM-detachment-induced necrosis.

Attributes

Attribute NameValues
URN
  • etd-04102015-162338

Author Cassandra Buchheit
Advisor Dr. Zachary Schafer
Contributor Dr. Siyuan Zhang, Committee Member
Contributor Dr. Crislyn DSouza-Schorey, Committee Member
Contributor Dr. Rebecca Wingert, Committee Member
Contributor Dr. Zachary Schafer, Committee Chair
Degree Level Doctoral Dissertation
Degree Discipline Biological Sciences
Degree Name PhD
Defense Date
  • 2015-03-27

Submission Date 2015-04-10
Country
  • United States of America

Subject
  • necrosis

  • inflammatory breast cancer

  • anoikis

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility and Access Public
Content License
  • All rights reserved

Departments and Units

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