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.

项目总结/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 在过去的五年里。它是源于但不是在初始应用中提出的工作的扩展。 本申请中详细介绍的项目将侧重于使用多OMIC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。 虽然这不是最初预期的，但我们发现胶质母细胞瘤细胞系和可能的胶质母细胞瘤 患者样本含有干细胞群体，其性质不同，特别是对 信号通路的激活和Rho家族小GTP酶Rac 1（Rac）和RhoA的激活。多- OMIC（转录组、蛋白质组和磷蛋白质组）分析细胞显示更大的侵入运动性 在中心工作中使用的生物模拟和临床相关RACE测定的背景下的行为， 似乎主要通过依赖于AKT-mTOR的激活的多种机制激活RhoA， RelB NF-κ B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以及不同的小GT3，Rac，拮抗 Rhoa.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，将分析扩展到表征每个表型的表观遗传特征， states.我们还将探索细胞运动行为是否可能在不同的微环境中改变， 有利于Rac依赖性而不是RhoA依赖性运动。此外，我们假设两种表型 状态可以促进侵入性扩散，但是通过脑组织内的不同途径，例如，通过， 血管空间与通过胼胝体或脑的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和组织模型中测试这一假设。我们预计 在这一费用延长项目期间进行的分析将大大提高我们对 大脑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。

项目成果

Programmable DNA repair with CRISPRa/i enhanced homology-directed repair efficiency with a single Cas9.

使用 CRISPRa/i 进行可编程 DNA 修复，通过单个 Cas9 增强同源定向修复效率

• DOI: 10.1038/s41421-018-0049-7
• 发表时间: 2018
• 期刊: Cell discovery
• 影响因子: 33.5
• 作者: Ye L;Wang C;Hong L;Sun N;Chen D;Chen S;Han F
• 通讯作者: Han F

The mammalian decidual cell evolved from a cellular stress response.

• DOI: 10.1371/journal.pbio.2005594
• 发表时间: 2018-08
• 期刊: PLoS biology
• 影响因子: 9.8
• 作者: Erkenbrack EM;Maziarz JD;Griffith OW;Liang C;Chavan AR;Nnamani MC;Wagner GP
• 通讯作者: Wagner GP

Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts.

• DOI: 10.1016/j.isci.2023.108593
• 发表时间: 2024-01-19
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Dighe, Anasuya;Maziarz, Jamie;Ibrahim-Hashim, Arig;Gatenby, Robert A.;Kshitiz;Levchenko, Andre;Wagner, Gunter P.
• 通讯作者: Wagner, Gunter P.

Evolution of placental invasion and cancer metastasis are causally linked

• DOI: 10.1038/s41559-019-1046-4
• 发表时间: 2019-12-01
• 期刊: NATURE ECOLOGY & EVOLUTION
• 影响因子: 16.8
• 作者: Kshitiz;Afzal, Junaid;Wagner, Gunter P.
• 通讯作者: Wagner, Gunter P.

Evolved Resistance to Placental Invasion Secondarily Confers Increased Survival in Melanoma Patients.

• DOI: 10.3390/jcm10040595
• 发表时间: 2021-02-05
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Suhail Y;Afzal J;Kshitiz
• 通讯作者: Kshitiz