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

基本信息

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
项目类别：
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

项目摘要

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

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（4）

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.

Targeting Pyruvate Kinase M2 Phosphorylation Reverses Aggressive Cancer Phenotypes.

DOI：
10.1158/0008-5472.can-20-4190
发表时间：
2021-08-15
期刊：
Cancer research
影响因子：
11.2
作者：
Apostolidi M;Vathiotis IA;Muthusamy V;Gaule P;Gassaway BM;Rimm DL;Rinehart J
通讯作者：
Rinehart J