Analysis of the regulatory networks regulating district stem cell-like states in aggressive cancers

项目摘要/摘要 这里提出的工作是耶鲁癌症系统生物学中心工作的延伸 在过去的五年里。它是源于但不是在最初的申请中提出的工作的延伸。 本申请中详述的项目将侧重于使用多组学方法来重建 规律性网络驱动癌细胞的表型可塑性，更具体地说，是癌症干细胞。 虽然这是最初没有预料到的，但我们发现胶质母细胞瘤细胞株和可能的胶质母细胞瘤 患者样本中含有不同性质的干细胞群体，特别是对 信号通路激活和Rho家族小GTP酶、rac1(Rac)和RhoA的激活。多种多样- 基因组(转录组、蛋白质组和磷蛋白质组)分析细胞表现出更大的侵袭性 在中心工作中使用的生物模拟和临床相关种族分析的背景下的行为， 似乎主要通过依赖于AKT-mTOR和AKT-mTOR激活的各种机制来激活RhoA RelB核因子-kappaB信号转导。另一方面，在这些条件下表现出较低运动性的细胞似乎 激活应激反应通路，特别是JNK和p38，以及一个独特的小GTP酶，Rac，拮抗 罗亚。这张图片将在项目过程中补充更多的实验和数据 分析工作，将分析扩展到表征每个表型的表观遗传特征 各州。我们还将探索细胞的运动行为是否会在不同的微环境中发生变化， 更倾向于依赖Rac而不是RhoA的运动性。此外，我们假设这两种表型 各州可能会促进侵入性传播，但通过脑组织内的不同途径，例如通过周围- 血管空间与通过胼胝体或大脑其他纤维性区域的纤维环境。我们会 在细胞微环境的各种工程和组织模型中测试这一假设。我们预料到 在这个成本延长项目中进行的分析将大大提高我们对 脑部和其他癌症的表型可塑性，并将为更智能的治疗铺平道路 癌症生长和侵袭性扩散。

Project Summary/Abstract The work proposed here is an extension of the work performed by the Yale Cancer Systems Biology Center over the last 5 years. It is an extension of the work stemming from but not proposed in the initial application. The project detailed in this application will focus on the use of multi-OMIC approaches to reconstruct the regularity networks driving phenotypic plasticity in cancer cells, and more specifically cancer stem cells. Although this was not initially anticipated, we discovered that glioblastoma cell line and possibly glioblastoma patient samples harbor stem cell populations that differ in their properties, particularly with respond to activation of signaling pathways and activation of Rho-family small GTPases, Rac1 (Rac) and RhoA. The multi- OMIC (transcriptomic, proteomic and phosphorus-proteomic) analysis cells displaying greater invasive motility behavior in the context of bio-mimetic and clinically relevant RACE assay used in the work of the Center, appear to primarily activate RhoA, through a variety of mechanisms relying on activation of AKT-mTOR and RelB NF-kappaB signaling. On the other hand, cell displaying lower motility under these conditions appear to activate stress response pathways, particularly JNK and p38 and a distinct small GTPase, Rac, antagonistic to RhoA. This picture will be supplemented over the course of the project with additional experimental and data analysis work, extending the analysis to characterization of epigenetic signatures of each of the phenotypic states. We will also explore whether the cell motility behavior may be altered in distinct micro-environments, favoring Rac-dependent rather RhoA-dependent motility. Furthermore, we hypothesize that both phenotypic states may promote invasive spread, but through distinct routes within the brain tissue, e.g., through peri- vascular spaces vs. through fibrous environment of corpus callosum or other fibrous areas of the brain. We will test this hypothesis in various engineered and tissue models of cellular micro-environments. We anticipate that the analysis undertaken during this cost extension project will substantially improve our understanding of the phenotypic plasticity in brain and other cancers and will pave the way to more intelligent treatments mitigating cancer growth and invasive spread.