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.

项目摘要/摘要这里提出的工作是耶鲁癌症系统生物学中心执行的工作的扩展在过去的5年中。这是源自初始应用中但未提出的作品的扩展。本应用程序中详细详细介绍的项目将重点介绍使用多摩管方法来重建规则性网络驱动癌细胞中表型可塑性，更具体地说是癌细胞。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是胶质母细胞瘤患者样品含有其特性不同的干细胞群体，尤其是对信号通路的激活和Rho-family小GTPases，Rac1（RAC）和RhoA的激活。多 OMIC（转录组，蛋白质组学和磷 - 蛋白质组）分析细胞显示出更大的侵入性运动在中心工作中使用的生物模拟和临床相关种族测定的背景下的行为，似乎主要通过依靠Akt-Mtor的激活和 relb nf-kappab信号传导。另一方面，在这些条件下显示较低运动的细胞似乎激活应力反应途径，尤其是JNK和P38，以及独特的小GTPase，RAC，与 Rhoa。这张图片将在项目的过程中补充其他实验和数据分析工作，将分析扩展到表型的表观遗传学特征的表征国家。我们还将探讨在不同的微环境中是否可以改变细胞运动行为，偏爱依赖RAC的相对于Rhoa依赖性运动。此外，我们假设两个表型状态可能会促进侵入性扩散，但是通过大脑组织内的不同路线，例如，通过血管空间与通过call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和组织模型中检验该假设。我们预料到这一点在此成本扩展项目中进行的分析将大大改善我们对大脑和其他癌症中的表型可塑性，将为更智能的治疗铺平道路癌症的生长和侵入性扩散。

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

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.

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.

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