Understanding the Metabolic Mechanisms Behind the Survival of Extracellular Matrix-Detached Breast Cancer Cells

Doctoral Dissertation

Abstract

Tumorigenic mammary epithelial cells have been found to gain the ability to survive in the absence of important signals provided by the extracellular matrix (ECM). However, the precise molecular mechanisms by which normal epithelial cells are able to gain the ability to survive without the ECM have yet to be unveiled. Likewise, the mechanisms in place to prevent the survival of non-tumorigenic cells detached from the ECM are also poorly characterized. Previous publications and work in our laboratory have found that there is a striking elevation in the levels of reactive oxygen species (ROS) when mammary epithelial cells are detached from the ECM. Interestingly, these increased levels of ROS result in the inhibition of fatty acid oxidation (FAO) and can contribute to the induction of cell death. These data suggest that detachment-induced ROS may be important in the prevention of survival of detached cells. In order to understand the implications of these studies, my project investigated the significance of metabolic regulation during ECM-detachment in cancer cells. My studies have uncovered a novel role for antioxidant enzymes in modulating metabolic activity and survival in ECM-detached breast cancer cells. In addition, these studies have unveiled a PI(3)K-dependent but AKT-independent signaling pathway involved in mediating metabolism and cell survival in detached cancer cells. Our data indicate that the critical effector downstream of PI(3)K is serum/glucocorticoid regulated kinase 1 (SGK-1). Together, our data strongly suggests that ECM-detached cancer cells must overcome detachment induced metabolic alterations in order to survive. Our work provides strong motivation for future studies investigating the importance of antioxidants and SGK-1 activation in ECM-detachment.

Attributes

Attribute NameValues
URN
  • etd-03252014-131717

Author Calli Anne Versagli
Advisor Zachary Schafer
Contributor Tracy Vargo-Gogola, Committee Member
Contributor Rebecca Wingert, Committee Member
Contributor Crislyn D'Souza-Schorey, Committee Member
Contributor Zachary Schafer, Committee Chair
Degree Level Doctoral Dissertation
Degree Discipline Biological Sciences
Degree Name PhD
Defense Date
  • 2014-03-21

Submission Date 2014-03-25
Country
  • United States of America

Subject
  • cell metabolism

  • breast cancer

  • SGK-1

  • oxidative stress

  • cell death

  • fatty acid oxidation

  • cancer metabolism

  • Cancer

  • Ras signaling

  • extracellular matrix detachment

  • AMPK

Publisher
  • University of Notre Dame

Language
  • English

Record Visibility Public
Content License
  • All rights reserved

Departments and Units

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