Interstitial Fluid Flow and the Glioma Tumor Microenvironment: Effects on Invasion and Therapeutic Outcomes

Sunday, December 31, 2017

11:00am - 12:00pm


310 Kelly Hall

Dr. Jennifer Munson
Department of Biomedical Engineering
University of Virginia

ABSTRACT:

Invasion of cancer cells is a primary mode of treatment resistance, and is an initiating step of metastatic spread. Though many cancers invade, glioblastoma, the deadliest form of brain cancer, is defined by the invasive nature of its cells. Invasion in the brain follows distinctive routes that correlate with interstitial and bulk flow pathways. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue. This differential leads to fluid transport specifically across the invasive edge of the tumor where cells are prone to both interact with the surrounding brain tissue and to evade localized, transport-limited therapies. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed a number of in vitro and in vivo methods to examine fluid flow responses. In vitro, we have found that interstitial flow can enhance invasion of brain cancer cells using both cell lines and patient-derived glioma stem cells in tissue-engineered models of the brain-tumor interface. These effects are mediated simultaneously by both chemotactic and mechanotransduction mechanisms. In vivo, we have seen interstitial flow both correlate and increase invasion of implanted cancer cells through the brain. By conducting in vivo measurements of interstitial flow, using MRI techniques, we have seen correlations between interstitial fluid flow and patterns of glial activation, extracellular matrix deposition, and receptor activation in tumor-associated brain along these invasive pathways. By examining molecular markers and cellular components distinctive in these flow regions, we can inhibit flow-stimulated invasion in patient-designed 3D tissue-engineered models. Further, the role of interstitial fluid flow in the response to therapies (radiation and chemotherapy) is multi-level, affecting both the transport of drugs and cellular resistance. These findings further implicate interstitial fluid flow as a driver of tissue morphology and indicate multiple mechanisms through which fluid flow can mediate cellular invasion and therapeutic outcomes.

BIOGRAPHY:

Dr. Munson completed her Ph.D. at Georgia Tech in Bioengineering followed by postdoctoral research at Ecole Polytechnique Federale de Lausanne in Switzerland. She's a Fulbright and Whitaker Alumna and started at the University of Virginia in 2014.