Deciphering mechanisms of perivascular tumor cell invasion in glioblastoma

描述（由申请人提供）：多形性胶质母细胞瘤（GBMs）是一种原发性脑肿瘤，具有侵袭性生长特性，与脉管系统紧密耦合。例如，茎样GBM细胞优先聚集在血管周围壁龛中，侵袭性GBM细胞通常通过血管基底膜分散在整个大脑中。此外，对GBM患者进行抗血管生成治疗通常会导致肿瘤细胞浸润增强和致命卫星病变的形成。在肿瘤进展和抗血管生成治疗过程中，GBM细胞与脑血管结合的分子机制在很大程度上仍然未知。在这个项目中，我们将研究GBM细胞如何利用由αvβ8整合素、其潜在的TGFβ细胞外基质（ECM）蛋白配体和TGFβ受体组成的特定细胞粘附和信号轴，选择性地促进脑内血管周围的生长和扩散。我们发现αvβ8整合素在侵袭性GBM细胞中表达，介导TGFβs的激活，驱动细胞极性和定向迁移。此外，αvβ8整合素蛋白在抗血管生成治疗后的侵袭性GBM细胞中高表达。基于这些数据，我们假设αvβ8整合素在肿瘤进展和抗血管治疗过程中调节促进GBM细胞侵袭的粘附和信号通路。此外，我们假设这些途径的抑制成分会减少GBM细胞的浸润。为了验证我们的假设，我们开发了一套独特的实验工具来(1)表征αvβ8整合素如何与VEGF-A受体Neuropilin-1相互作用以促进GBM细胞浸润；(2)研究整合素激活的tgf - βs如何与VEGF-A协同驱动GBM细胞侵袭；(3)在临床前小鼠GBM模型中选择性抑制这些通路的组分以阻断其侵袭性。总的来说，这些实验不仅将阐明GBM细胞中αvβ8整合素激活的tgf - βs和VEGF-A受体之间的新联系，而且可能最终导致新的治疗策略来抑制肿瘤进展过程中的细胞侵袭

DESCRIPTION (provided by applicant): Glioblastoma multiformes (GBMs) are primary brain tumors displaying invasive growth properties that are tightly coupled to the vasculature. For example, stem-like GBM cells preferentially cluster in perivascular niches and invasive GBM cells often disperse throughout the brain via vascular basement membranes. Furthermore, anti-angiogenesis therapies administered to patients with GBM often lead to enhanced tumor cell infiltration and the formation of lethal satellite lesions. The molecular mechanisms that couple GBM cells to cerebral blood vessels during tumor progression and following anti-angiogenesis therapies remain largely unknown. In this project we will investigate how GBM cells exploit a specific cell adhesion and signaling axis comprised of αvβ8 integrin, its latent TGFβ extracellular matrix (ECM) protein ligands, and TGFβ receptors to selectively promote perivascular growth and dispersal in the brain. We have discovered that αvβ8 integrin is expressed in invasive GBM cells where it mediates activation of TGFβs to drive cell polarity and directional migration. In addition, αvβ8 integrin protein is highly expressed in invasive GBM cells following anti-angiogenesis treatments. Based on these data we hypothesize that αvβ8 integrin regulates adhesion and signaling pathways that promote GBM cell invasion during tumor progression and following anti-vascular therapies. Furthermore, we hypothesize that inhibiting components of these pathways will diminish GBM cell infiltration. To test our hypotheses we have developed a unique set of experimental tools to (1) characterize how αvβ8 integrin interacts with the VEGF-A receptor Neuropilin-1 to promote GBM cell infiltration; (2) investigate how integrin-activated TGFβs cooperate with VEGF-A to drive GBM cell invasiveness; and (3) selectively inhibit components of these pathways to block invasiveness in pre-clinical mouse models of GBM. Collectively, these experiments will not only elucidate novel links between αvβ8 integrin-activated TGFβs and VEGF-A receptors in GBM cells, but may eventually lead to new therapeutic strategies for inhibiting cell invasion during tumor progression and following anti-vascular therapies.