November 30th CTE Seminar

Guest Speaker

Title: Interstitial fluid flow in the brain tumor microenvironment

Presenter: Dr. Jennifer Munson,

Research group: Onco-Engineering Lab

Fluid flow in the brain is an emerging area of research with implications in Alzheimers, aging, brain homeostasis, development, and cancer. Glioblastoma is the deadliest form of brain cancer and 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, there is increased interstitial fluid flow, or fluid flow within the extracellular matrix between cells within the tissue. This increased fluid flow develops due to an 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 in- terstitial fluid flow affects the invasion of brain cancer cells, we have developed a number of in vitro and in vivo methods to examine interstitial 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 3D tissue-engineered models of the brain-tumor interface. These effects are both mediated simultaneously by chemotactic, via CXCR4-CXCL12 signaling, and mechanotrans- duction, via CD44-hyaluronan, mechanisms. In murine models of glioblastoma, we have seen that convection enhanced delivery increases invasion of implanted cancer cells through the brain and that invasion correlates with regions of flow. By conducting in vivo measurements of interstitial flow, using MRI techniques, we have identified specific flow velocities and correlated interstitial fluid flow to patterns of glial activation, extracellular matrix deposition, and receptor activation in tumor-associated brain along these invasive pathways. 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. In this talk, I will discuss the nature and implications of inter- stitial fluid flow in the brain, primarily in the context of cancer, identifying both tissue-level and cellular-level mechanisms.