Abstract LB-96: Extrinsic and intrinsic force and GBM aggression

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Despite concerted effort the mean survival time for patients with aggressive GBM remains unchanged with a mean of 14 months. Indeed, high grade GBMs are notoriously resistant to therapy and typically disseminate throughout the brain tissue, severely compromising patient treatment. In this respect, the most lethal GBMs arise within the SVZ region of the brain which is rich in stem cells. This has lead to speculation that GBM aggression is related to their stem-like origin. Consistently, using AFM indentation we determined that analogous to neural stem cells (NSCs), high grade GBMs are very soft and express high levels of the Notch regulated gene HES-1. We also found that high grade GBMs and NSCs both express elevated levels of the stemness-promoting repressor NCoR2. We further determined that NCoR2 expression correlates with poor GBM patient prognosis, which is an observation that accords with our recent finding that NCoR2 enhances breast tumor survival in response to radiation, chemotherapy and immune activators in vitro and in vivo. These findings are consistent with a stem-like origin for GBMs and identify NCoR2 as a putative unique survival mechanism that could explain the treatment resistance of this disease. Interestingly, AFM measurements of freshly excised murine brain tumor slices showed that GBMs arising within the SVZ region are also quite stiff. Preliminary findings also showed that isolated high grade GBM cells but not low grade oligodendroglioma cells have a greatly enhanced mechano-responsiveness e.g. they spread more on soft gels and possess a vastly altered glycocalyx; traits that predict elevated contractility and integrin signaling. Given MRI data indicating very aggressive GBMs in the SVZ region are highly vascularized and experience elevated compression the findings support the idea that tumors that arise within this highly mechanically-challenged SVZ microenvironment have a unique mechano-behavior that could facilitate their growth, survival and dissemination. Indeed, the high compliance, contractility and mechanical resistance of GBMs would facilitate their growth, survival and expansion within compressed brain tissue and would foster their ability to navigate and disseminate into the dense GBM-associated ECM. Because reducing tumor force can revert the malignant phenotype of cancerous tissue and will reduce tumor cell invasion, growth, and survival and inhibit tumor progression and decrease tumor incidence we predict that the altered force microenvironment and intrinsic mechanobehavior of GBMs contribute to their aggression. Consequently, studies are now underway to clarify the interplay between cell and tissue force and GBM behavior and to determine the relevance of NCoR2 to GBM treatment resistance. (Supp by: NCI grants U54CA143836–01 and NIH/NCI R01 CA138818–01A1 to V.M.W. and a National Science Foundation (GRFP) Fellowship to Y.A.M.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-96. doi:10.1158/1538-7445.AM2011-LB-96