ECM geometrical and mechanical properties modulate RTK signaling

ECM 几何和机械特性调制 RTK 信号

基本信息

批准号：
9763512
负责人：
JAY T. GROVES
金额：
$ 62.01万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-22 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763512
关键词：
3-Dimensional Adhesions Aggressive behavior Biochemical Biological Assay Bioreactors Cancer Patient Cell membrane Cells Characteristics Chemicals Clinical Coupling Cues Development Dimensions Disease Electron Microscopy Engineering Enzymes Eph Family Receptors Epidermal Growth Factor Receptor Epigenetic Process Epithelial Epithelial-Stromal Communication Event Extracellular Matrix Failure Fluorescence Resonance Energy Transfer Genetic Genetic Variation Geometry Glycocalyx Goals Guanosine Triphosphate Phosphohydrolases Heterogeneity Hybrids Hypoxia Incidence Integrins Interference Microscopy Ligands Lipid Bilayers Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mammary Neoplasms Mammary gland Maps Measurement Mechanics Mediating Membrane Membrane Lipids Methods Molecular Mutate Mutation Nature Pancreas Patients Pattern Probability Process Protein Dynamics Proteins Ras/Raf Reaction Receptor Activation Receptor Protein-Tyrosine Kinases Recurrence Resistance Resistance development Scanning Science Signal Pathway Signal Transduction Somatic Mutation Son of Sevenless Proteins Surface Survival Rate System Techniques Testing Therapeutic Tissues Transgenic Mice Tumor Tissue Tyrosine Kinase Inhibitor Work Xenograft procedure base cancer cell experimental study in vivo inhibitor/antagonist insight live cell imaging malignant breast neoplasm mechanical properties membrane reconstitution mouse model mutant nanofabrication novel overexpression pancreatic neoplasm public health relevance receptor receptor function reconstitution recruit response single molecule targeted treatment therapeutic target therapy design therapy resistant transmission process treatment response triple-negative invasive breast carcinoma tumor tumor behavior tumor microenvironment tumor progression two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Receptor tyrosine kinase (RTK) amplification or inappropriate activation of one or more components of the RTK signaling pathway occur in many aggressive, treatment resistant tumors including triple negative breast cancer, and lung and pancreatic cancers. The clinical importance of RTK signaling has motivated the development of targeted therapies designed to block receptor activation and downstream signal transmission. RTK inhibitors can have dramatic short-term benefits, however patients frequently present with recurrent, RTK inhibitor resistant tumors. Our goal is to understand the fundamental origins of this therapeutic failure. Treatment resistance can arise due to cell-to-cell genetic or epigenetic RTK signaling heterogeneity. The extracellular matrix (ECM) tumor microenvironment is physically and biochemically heterogeneous and we and others find that the spatial-mechanical features of the ECM exert profound effects on RTK signaling. It is our thesis that in addition to genetic variation, external spatial-mechanical factors from the ECM are a critical cause of RTK therapy resistance. We predict that ECM environmental niches may protect some cancer cells from RTK inhibitor treatments, thus favoring the survival of tumor clones and enhancing the probability of these malignant cells developing `beneficial' mutations that increase their aggression and ultimately compromise patient survival. Yet, the molecular mechanisms whereby spatial-mechanical cues from the ECM regulate RTK signaling remain unclear. The Groves lab has developed robust supported lipid membrane platforms to study dynamics of proteins in signaling assemblies, both in reconstitution and in hybrid junctions with living cells. Using these systems Groves and colleagues demonstrated that the spatial organization of RTKs and their effectors at the plasma membrane modulate signal transduction initiation. The Weaver group has an arsenal of 2- and 3-dimensional organotypic culture systems and a suite of novel transgenic mouse models in which ECM mechanics and topography and the glycocalyx can be controlled, enabling precision studies in culture and in vivo. Weaver showed that ECM mechanics and topography and a hypoxia induced bulky glycocalyx alter RTK signaling; likely by altering membrane geometry and RTK effector activity. Here Groves and Weaver combine their expertise to test specific molecular mechanisms by which spatial-mechanical cues from the ECM alter RTK signaling. They will focus on Ras; a GTPase as a key RTK signaling node and interrogate the impact of physical modulations on Ras activation in their lipid bilayer, cellular, and in vivo platforms. These studies will reveal te molecular mechanisms by which the cellular microenvironment modulates RTK signaling and contributes to treatment resistance. From this understanding, the molecular mechanisms of coupling themselves will emerge as new targets to reduce incidence of RTK inhibitor resistance in cancer patients.

描述（由申请人提供）：受体酪氨酸激酶（RTK）扩增或 RTK 信号通路的一种或多种成分的不适当激活发生在许多侵袭性、难治性肿瘤中，包括三阴性乳腺癌、肺癌和胰腺癌。 RTK 信号传导的研究推动了旨在阻断受体激活和下游信号传递的靶向治疗的发展，RTK 抑制剂可以带来显着的短期益处，但患者经常出现复发性 RTK 抑制剂耐药性肿瘤。目标是了解这种治疗失败的根本原因可能是由于细胞间的差异而产生的。遗传或表观遗传 RTK 信号异质性。细胞外基质 (ECM) 肿瘤微环境在物理和生化方面具有异质性，我们和其他人发现，除了遗传因素外，ECM 的空间机械特征对 RTK 信号也有深远的影响。变异，来自 ECM 的外部空间机械因素是 RTK 治疗抵抗的关键原因，我们预测 ECM 环境生态位可能会保护一些癌细胞免受 RTK 抑制剂治疗，从而有利于肿瘤克隆的生存。并增加这些恶性细胞产生“有益”突变的可能性，从而增加其攻击性并最终损害患者的生存。然而，来自 ECM 的空间机械线索调节 RTK 信号传导的分子机制仍不清楚。 Groves 及其同事使用这些系统研究信号组装体中蛋白质的动态，包括在与活细胞的重建和混合连接中的膜平台，证明 RTK 及其效应器在质膜上的空间组织可调节信号。 Weaver 团队拥有一系列 2 维和 3 维器官型培养系统以及一套新型转基因小鼠模型，其中 ECM 力学、拓扑结构和糖萼可以被控制，从而能够在培养和体内进行精确研究。 ECM 力学和地形以及缺氧诱导的庞大糖萼可能通过改变膜几何形状和 RTK 效应器活性来改变 RTK 信号传导；格罗夫斯和韦弗在此结合他们的专业知识进行测试。 ECM 的空间机械线索改变 RTK 信号传导的特定分子机制；他们将关注 Ras 作为关键 RTK 信号传导节点，并探究物理调节对其脂双层、细胞和体内 Ras 激活的影响。这些研究将揭示细胞微环境调节 RTK 信号传导并导致治疗耐药的分子机制，根据这一认识，耦合本身的分子机制将成为减少 RTK 抑制剂耐药发生率的新靶点。癌症患者。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Probing the effect of clustering on EphA2 receptor signaling efficiency by subcellular control of ligand-receptor mobility.

通过配体-受体迁移率的亚细胞控制探讨聚类对 EphA2 受体信号传导效率的影响。

DOI：
发表时间：
2021
期刊：
影响因子：
7.7
作者：
Chen, Zhongwen;Oh, Dongmyung;Biswas, Kabir Hassan;Zaidel;Groves, Jay T
通讯作者：
Groves, Jay T

Nanopore-mediated protein delivery enabling three-color single-molecule tracking in living cells.

纳米孔介导的蛋白质递送实现了活细胞中的三色单分子追踪。

DOI：
发表时间：
2021
期刊：
影响因子：
11.1
作者：
Chen, Zhongwen;Cao, Yuhong;Lin, Chun;Alvarez, Steven;Oh, Dongmyung;Yang, Peidong;Groves, Jay T
通讯作者：
Groves, Jay T

Dynamic Scaling Analysis of Molecular Motion within the LAT:Grb2:SOS Protein Network on Membranes.

膜上 LAT:Grb2:SOS 蛋白质网络内分子运动的动态缩放分析。

DOI：
发表时间：
2017-10-17
期刊：
影响因子：
3.4
作者：
Huang, William Y C;Chiang, Han;Groves, Jay T
通讯作者：
Groves, Jay T

K-Ras4B Remains Monomeric on Membranes over a Wide Range of Surface Densities and Lipid Compositions.

K-Ras4B 在各种表面密度和脂质成分的膜上保持单体。

DOI：
发表时间：
2018
期刊：
影响因子：
3.4
作者：
Chung, Jean K;Lee, Young Kwang;Denson, John;Gillette, William K;Alvarez, Steven;Stephen, Andrew G;Groves, Jay T
通讯作者：
Groves, Jay T

EGFR family and Src family kinase interactions: mechanics matters?

EGFR 家族和 Src 家族激酶相互作用：机制重要吗？

DOI：
发表时间：
2018
期刊：
影响因子：
7.5
作者：
Chen, Zhongwen;Oh, Dongmyung;Dubey, Alok Kumar;Yao, Mingxi;Yang, Beverly;Groves, Jay T;Sheetz, Michael
通讯作者：
Sheetz, Michael