This application address broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06- CA-116: Physical Sciences and Cellular Mechanics The ability of malignant glioma cells to invade normal brain severely limits all current therapies for this devastating disease. Blocking this process could therefore convert gliomas from an invasive, whole brain disease to a local disease-one that could be effectively treated with current local therapies, such as surgery or collimated radiation therapy. Thus, there is a pressing need to develop effective anti-invasive treatments. However, doing so will require a detailed understanding of the mechanics of glioma movement and invasion. To address this issue, Drs. Odde and Rosenfeld recently initiated a collaboration to develop computational models for the mechanochemical basis of glioma motility and in vitro models for brain micromechanics and microarchitecture. We have compelling preliminary results, described below, which show that on substrates of high stiffness, glioma cells move in a manner very similar to what we have described in in vivo brain invasion, while on substrates of low stiffness, they diverge significantly. We now propose to extend these studies to understand the fundamental mechanics of glioma motility to ultimately control the process of glioma dispersion in brain cancer patients. Our initial studies will aim to meet the following challenges: 1) Develop predictive computational models for glioma migration as a function of environmental mechanical stiffness and micro-architecture 2) Develop in vitro microsystems to mimic in vivo micro-architecture and mechanical properties 3) Measure the brain micromechanical properties that are sensed by migrating gliomas We believe that our collaboration will have a high impact because it spans a broad range of scientific themes-- from basic modeling of cell mechanics and engineering of in vivo-like microsystems (Odde) to in vivo motility and animal studies (Rosenfeld). Furthermore, since Dr. Rosenfeld also directs one of the largest brain tumor clinical research centers in the Northeast, we are well positioned to ultimately translate our findings into early stage clinical trials. We believe that this recently initiated collaboration, which brings together modeling, microsystems, cell biology, animal model development of malignant gliomas, and clinical neuro-oncology, is unique. By addressing these challenges, we will be in position to develop predictive models for glioma migration in rodent brain slices, and ultimately in intact human brains. Our goal will be to use these mechanochemical models for glioma migration to guide development of novel therapeutic strategies to interfere with glioma dispersion within the brain.
Brain cancer is a devastating disease due to the progressive spreading of cancer cells throughout the brain. We will develop fundamentally new tools for understanding the mechanical basis of brain cancer cell movement, which will then guide novel therapeutic strategies.
|Bangasser, Benjamin L; Shamsan, Ghaidan A; Chan, Clarence E et al. (2017) Shifting the optimal stiffness for cell migration. Nat Commun 8:15313|
|Klank, Rebecca L; Decker Grunke, Stacy A; Bangasser, Benjamin L et al. (2017) Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level. Cell Rep 18:23-31|
|Bangasser, Benjamin L; Rosenfeld, Steven S; Odde, David J (2013) Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. Biophys J 105:581-92|
|Bangasser, Benjamin L; Odde, David J (2013) Master equation-based analysis of a motor-clutch model for cell traction force. Cell Mol Bioeng 6:449-459|
|Mogilner, Alex; Odde, David (2011) Modeling cellular processes in 3D. Trends Cell Biol 21:692-700|