Consequence of collective cell invasion in glioblastoma

 描述（由申请人提供）：肿瘤细胞侵袭，即肿瘤细胞脱离原发肿瘤并扩散到远处器官的过程，是向更晚期疾病转变的信号，并极大地促进了许多癌症类型的致死性。单个肿瘤细胞的迁移已经得到了很好的描述，但越来越多的证据表明，肿瘤细胞也作为一个集体迁移，或一组细胞通过细胞连接保持粘附和通信。据报道，作为集体迁移的细胞更深入地侵入器官并分散到多种组织类型中。最常见的恶性脑肿瘤胶质母细胞瘤（GBM）的一个标志是肿瘤细胞侵入脑实质，这一特征极大地导致了治疗后肿瘤复发率高。我们无法成功治疗GBM也是由称为癌症干细胞（CSC）的自我更新细胞的治疗抗性群体的存在所驱动的。与非干细胞肿瘤细胞（non-CSC）相比，CSC已显示出增强的迁移能力，尽管CSC入侵的机制和这种入侵的后果尚未确定。该项目的翻译目标是对CSC的集体细胞迁移进行机制研究，并确定这种入侵对GBM进展的影响。基于我们显示CSC的集体细胞迁移的初步数据，我们假设集体细胞侵袭对于GBM生长是必不可少的，并且可以通过损害控制集体细胞侵袭的分子过程来破坏。为了深入了解这些分子过程，我们在果蝇中进行了筛选，并确定了负责集体入侵的新基因。使用一个综合的方法跨越果蝇发育到人类CSC模型，我们将通过研究以下目标来询问这个假设：1）集体入侵需要动态的细胞-细胞连接和粘附，2）破坏集体细胞入侵会降低GBM生长并增加标准治疗的疗效。该项目的长期目标是将获得的关于GBM CSC的集体细胞迁移和侵袭的信息转化为可用作临床治疗的抑制策略。

 DESCRIPTION (provided by applicant): Tumor cell invasion, the process by which tumor cells break away from the primary tumor and spread to distant organs, signals a transition to more advanced disease and greatly contributes to the lethality of many cancer types. The migration of single tumor cells has been well described, but mounting evidence suggests that tumor cells also migrate as a collective, or a group of cells that maintain adhesion and communication through cellular junctions. Cells migrating as a collective have been reported to invade more deeply into organs and to disperse into multiple tissue types. One hallmark of the most common malignant brain tumor, glioblastoma (GBM), is the invasion of tumor cells into the brain parenchyma, a characteristic that greatly contributes to the high rate of tumor recurrence after therapy. Our inability to successfully treat GBM is also driven by the presence of a therapeutically resistant population of self-renewing cells termed cancer stem cells (CSCs). CSCs have been shown to have an enhanced ability to migrate compared with non-stem tumor cells (non-CSCs), although the mechanisms by which CSCs invade and the consequences of this invasion have yet to be determined. The translational goal of this project is to conduct mechanistic studies into collective cell migration by CSCs and to determine the impact of this invasion on GBM progression. Based on our preliminary data showing collective cell migration of CSCs, we hypothesize that collective cell invasion is essential for GBM growth and can be disrupted by compromising the molecular processes governing collective cell invasion. To gain insight into these molecular processes, we performed a screen in Drosophila and identified novel genes responsible for collective invasion. Using an integrative approach spanning Drosophila development to human CSC models, we will interrogate this hypothesis by investigating the following aims: 1) that collective invasion requires dynamic cell-cell junctions and adhesion and 2) that disrupting collective cell invasion decreases GBM growth and increases the efficacy of standard-of-care therapy. The long-term goal of this project is to translate the information gained about collective cell migration and invasion of GBM CSCs to inhibition strategies useful as clinical therapies.