DATE: March 22, 2018
TIME: 09:00am PDT, 12:00pm EDT

Mechanobiology of Glioblastoma-Initiating Cells

Glioblastoma (GBM) is the most aggressive primary brain cancer, with nearly universal recurrence after treatment. GBMs are highly heterogeneous at the cellular level, and there is much evidence that recurrence, chemoresistance, and invasion are driven by a rare and specialized population of tumor initiating cells (TICs) within the tumor. These TICs are thought to share some similarities with stem cells in that they can both self-renew and differentiate to produce a range of cell types found in the bulk tumor. Because glioblastoma is above all a disease of tissue invasion and because invasion involves complex mechanical signaling between the microenvironment and the invading cells, we probed how TICs respond to mechanical cues. We found that in contrast to the majority of other cell types, TICs surprisingly showed very little stiffness-dependent change in cell shape and migration. Furthermore, we found that by increasing cellular force generation we could increase mechanosensitivity and extend survival in a mouse xenograft model. We next asked how the mechanosensitivity of these TICs changes as they are exposed to bone morphogenetic protein 4 (BMP4), which has been previously shown to elicit a differentiation-like effect on GBM TICs and extend survival in a xenograft model. We found that TICs treated with BMP4 showed increased stiffness-dependent changes in cell shape and reduced tissue invasion. We next performed RNA sequencing for a systems-level picture of how differentiation impacts mechanical signaling in TICs. We identified several pathways that showed mechanically-regulated changes impacted by differentiation, particularly those governing cell-extracellular matrix adhesions. These findings demonstrate that manipulation of mechanotransductive signaling can be leveraged to control tumor growth and invasion, and provide insight on alterations in mechanical signaling in stem-like and differentiated tumor initiating cells.

Learning Objectives:

• Understand the role of tumor initiating cells (TICs) in glioblastoma (brain) cancers
• Learn how the sensitivity of TICs to mechanical cues at the transcriptomic level and at the phenotypic level influences tumor growth and invasion.