The Contribution of Malignant Ascites in Regulating Ovarian Cancer Metastasis

Doctoral Dissertation
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Abstract

Ovarian cancer (OvCa) is the most fatal gynecological malignancy and the 5th leading cause of cancer death among U.S women. The peritoneal cavity is the main metastatic route in OvCa. Malignant ascites buildup in the peritoneal cavity is a common symptom in OvCa with more than one-third of OvCa patients present with ascites at the time of diagnosis and almost all patients with recurrent disease develop ascites. Malignant ascites can reach >2 liters, contributing to poor quality of life and to mortality in OvCa patients. The molecular components of malignant ascites may play a significant role in OvCa progression through influencing OvCa cell behavior and preparing a receptive environment for OvCa metastasis. Additionally, the malignant ascites buildup elevates the intra-peritoneal pressure (IPP) and alters the mechanobiology of the peritoneal microenvironment, impacting OvCa metastatic success. Yet, a complete understanding of the mechanisms through which malignant ascites promotes OvCa progression is lacking. In this work, we used a panel of in vitro, ex vivo and in vivo assays to explore (i) the role of ascites-upregulated Wnt5a protein in promoting OvCa progression and (ii) the alterations induced by ascites-elevated IPP that contribute to the disease progression. Our data identified Wnt5a as a host peritoneal-secreted factor that potentiates OvCa cell pro-metastatic behavior. Depletion of Wnt5a in host cells significantly altered OvCa cell pro-metastatic behavior, reduced tumor burden and metastasis in mice and induced an anti-tumor immune microenvironment in ovarian tumors. Our data also shows ascites-induced compression significantly enhances OvCa cell adhesion to peritoneum and altered the peritoneal ultrastructure. Furthermore, compression promoted the interaction between OvCa cells and peritoneal mesothelial cells (MC) through the induction of tunneling nanotube (TNT) formation, which modulated the transport of mitochondria from MC to OvCa cell. Additionally, compression induced the remodeling of the peritoneal collagen fibers into a straight and anisotropic alignment, a collagen alignment signature that is correlated with enhanced invasion in solid tumors. Collectively, these findings elucidate new roles of ascites-induced IPP in promoting OvCa progression. This work highlights Wnt5a as a potential therapeutic target in OvCa and reveals new roles played by malignant ascites in promoting OvCa progression.

Attributes

Attribute NameValues
Author Marwa S Asem
Contributor Brian Blagg, Committee Member
Contributor M. Sharon Stack, Research Director
Contributor Katharine White , Committee Member
Contributor Holly Goodson, Committee Member
Contributor Tracy Vargo-Gogola, Committee Member
Degree Level Doctoral Dissertation
Degree Discipline Integrated Biomedical Sciences
Degree Name Doctor of Philosophy
Banner Code
  • PHD-IBCH

Defense Date
  • 2019-06-13

Submission Date 2019-07-05
Record Visibility and Access Public
Content License
  • All rights reserved

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