Advisory Committee Chair
Mary Kathryn Sewell-Loftin
Advisory Committee Members
Karthikeyan Mythreye
Palaniappan Sethu
Rebecca Arend
Salvarangan Ponnazhagan
Document Type
Dissertation
Date of Award
1-1-2025
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Ovarian cancer is the most lethal gynecological cancer, but despite this, the effects of the ovarian tumor microenvironment (TME) on disease progression are poorly understood. The TME consist of the extra cellular matrix (ECM), cellular components, and mechanical forces. Cancer associated fibroblasts (CAFs) are stromal cells that secrete several ECM components including collagen, fibronectin, and hyaluronic acid (HA). CAFs also have increased motility and contractility, this increased movement creates micro-strains experienced by the tumor cells in the TME. HA interacts with cancer cells as both a serum and stromal component. Increases in stromal HA in the ovarian TME are associated with a more progressed disease state and a worse 5-year survival rate, but serum HA does not have these same correlations. HA influences cancer cell behaviors through cell surface receptor CD44. The intracellular domain of CD44 interacts with Src which links CD44 to oncogenic pathways including MAPK, PI3K, and Rho/Roc. Through these mechanisms, the HA/CD44 signaling axis alters ovarian cancer cell proliferation, invasion, and drug resistance. It is known that Src is mechanically sensitive but the mechanism in which HA plays a role in this sensitivity is not well characterized. We hypothesize that tension through HA in the ovarian TME alters CD44 signaling and further downstream functional outcomes. In a 2D platform we modeled the combined effects of tensile strain and serum or stromal HA. We evaluated altered CD44 and downstream Src expression and expanded our studies into a complex microphysiological system that allowed us to evaluate how combined strain and stromal-like HA alter CD44 functional effects including proliferation, migration, and response to chemotherapy treatment. Our results show that a stromal-like HA presentation works synergistically with tensile strain to increase CD44 expression and increase pro-cancer cellular behaviors. These results highlight the importance of including not only biochemical but also biomechanical factors when modeling ovarian cancer. Our findings help elucidate the role of the TME in disease progression and gives valuable insight for potential therapeutics that target the HA/CD44 axis.
Recommended Citation
Kramer, Maranda Erin, "Synergistic Effects Of Hyaluronic Acid And Mechanical Strain On Ovarian Cancer Cell Behaviors" (2025). All ETDs from UAB. 6859.
https://digitalcommons.library.uab.edu/etd-collection/6859
Comments
etdadmin_upload_1142090