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

侵袭性癌症中调节区域干细胞样状态的调节网络分析

• 批准号: 10407391
• 负责人: Andre Levchenko
• 金额: $ 42.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407391
• 关键词: Area; Automobile Driving; Behavior; Biological Assay; Biomimetics; Brain; Brain Neoplasms; Cell Line; Cell model; Cells; Corpus Callosum; Data Analyses; Environment; Epigenetic Process; FRAP1 gene; Family; Glioblastoma; Growth; Intelligence; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of brain; Monomeric GTP-Binding Proteins; NF-kappa B; Pathway interactions; Patients; Phenotype; Phosphorus; Property; Proteomics; Proto-Oncogene Proteins c-akt; Route; Sampling; Signal Pathway; Signal Transduction; Systems Biology; Testing; Tissue Engineering; Work; biological adaptation to stress; brain tissue; cancer cell; cancer stem cell; cell motility; clinically relevant; cost; experimental analysis; improved; multiple omics; p38 Mitogen Activated Protein Kinase; rho; stem; stem cell population; stem-like cell; transcriptomics

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.

项目概要/摘要 这里提出的工作是耶鲁大学癌症系统生物学中心所做工作的延伸 过去5年。它是源于最初申请但未在最初申请中提出的工作的延伸。 本申请中详细介绍的项目将重点关注使用多 OMIC 方法来重建 规律性网络驱动癌细胞，更具体地说是癌症干细胞的表型可塑性。 尽管最初没有预料到这一点，但我们发现胶质母细胞瘤细胞系和可能的胶质母细胞瘤 患者样本中含有特性不同的干细胞群，特别是对 信号通路的激活以及 Rho 家族小 GTPase、Rac1 (Rac) 和 RhoA 的激活。多 OMIC（转录组学、蛋白质组学和磷蛋白质组学）分析细胞显示出更强的侵袭性 中心工作中使用的仿生和临床相关 RACE 测定背景下的行为， 似乎主要通过依赖于 AKT-mTOR 激活的多种机制来激活 RhoA RelB NF-kappaB 信号传导。另一方面，在这些条件下表现出较低运动性的细胞似乎 激活应激反应途径，特别是 JNK 和 p38 以及一种独特的小 GTP 酶 Rac，拮抗 罗阿。这张图片将在项目过程中补充额外的实验和数据 分析工作，将分析扩展到每个表型的表观遗传特征的表征 州。我们还将探索细胞运动行为是否可能在不同的微环境中发生改变， 有利于 Rac 依赖性而非 RhoA 依赖性运动。此外，我们假设这两种表型 状态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区域的纤维环境。我们将 在细胞微环境的各种工程模型和组织模型中检验这一假设。我们预计 在这个成本扩展项目期间进行的分析将大大提高我们对 脑癌和其他癌症的表型可塑性将为更智能的治疗方法铺平道路 癌症生长和侵袭性扩散。

项目成果

Diversity in cancer invasion phenotypes indicates specific stroma regulated programs.

癌症侵袭表型的多样性表明特定的基质调节程序。

• 发表时间: 2021-01
• 影响因子: 4.3
• 作者: Novin, Ashkan;Suhail, Yasir;Ajeti, Visar;Goyal, Ruchi;Wali, Khadija;Seck, Atta;Jackson, Ale;Kshitiz
• 通讯作者: Kshitiz

Evolution of placental invasion and cancer metastasis are causally linked.

胎盘侵袭的演变和癌症转移之间存在因果关系。

• 发表时间: 2019
• 影响因子: 16.8
• 作者: Kshitiz;Afzal, Junaid;Maziarz, Jamie D;Hamidzadeh, Archer;Liang, Cong;Erkenbrack, Eric M;Kim, Hong Nam;Haeger, Jan;Pfarrer, Christiane;Hoang, Thomas;Ott, Troy;Spencer, Thomas;Pavličev, Mihaela;Antczak, Douglas F;Levchenko, Andre;Wagner
• 通讯作者: Wagner

Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations.

机械化学反馈是不同细胞群内性质不同的细胞极性模式共存的基础。

• 发表时间: 2017-07-11
• 影响因子: 11.1
• 作者: Park, JinSeok;Holmes, William R;Lee, Sung Hoon;Kim, Hong;Kim, Deok;Kwak, Moon Kyu;Wang, Chiaochun Joanne;Edelstein;Levchenko, Andre
• 通讯作者: Levchenko, Andre

Programmable sequential mutagenesis by inducible Cpf1 crRNA array inversion.

通过诱导型 Cpf1 crRNA 阵列倒转进行可编程序贯诱变。

• 发表时间: 2018
• 影响因子: 16.6
• 作者: Chow, Ryan D;Kim, Hyunu Ray;Chen, Sidi
• 通讯作者: Chen, Sidi

Decidualization of Human Endometrial Stromal Fibroblasts is a Multiphasic Process Involving Distinct Transcriptional Programs.

人子宫内膜基质成纤维细胞的蜕膜化是一个涉及不同转录程序的多相过程。

• 发表时间: 2019
• 作者: Rytkönen, Kalle T;Erkenbrack, Eric M;Poutanen, Matti;Elo, Laura L;Pavlicev, Mihaela;Wagner, Günter P
• 通讯作者: Wagner, Günter P