Attacking stress tolerance in cancer

攻击癌症的压力耐受性

基本信息

批准号：
10062746
负责人：
DAVID A CHERESH
金额：
$ 11.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-18 至 2025-08-31
项目状态：
未结题

项目摘要

Project Summary/Abstract My career began with the identification of cell surface markers on invasive cells, and led to the discovery of how integrins αvβ3 and αvβ5 on endothelial cells respond to cues within the tumor microenvironment to promote angiogenesis. I later demonstrated that αV integrins on tumor cells use these same fundamental pathways to achieve aggressive, invasive, and metastatic behavior. Now, my R35 proposal represents a further evolution of these concepts to ask how tumor cells undergo reprogramming in response to cellular stresses, including hypoxia, nutrient deprivation, or cancer therapy. We find that αvβ3 expression can be induced by stress to reprogram tumor cells toward a stress-tolerant, drug-resistant, stem-like state that is associated with tumor progression and metastasis for a wide range of cancers. Because individual tumors use this integrin to overcome unique challenges, we will define how αvβ3 activates downstream effectors that vary between tumor type, genetic profile, and microenvironment. The overall goal of my future research program is to understand how such tumors use integrin αvβ3 to gain stress tolerance so that we can devise ways to attack this process therapeutically. This proposed research will not only lead to a fundamental understanding of how tumors adapt to therapy or microenvironmental stress, but it should identify new druggable targets to limit cancer progression by preventing or overcoming tumor cell drug resistance and stress tolerance.

项目摘要/摘要我的职业始于在侵入性细胞上识别细胞表面标记，并发现内皮细胞上整联蛋白αVβ3和αVβ5如何响应肿瘤微环境内的提示促进血管生成。后来我证明了肿瘤细胞上的αV整合蛋白使用这些相同的基本实现侵略性，侵入性和转移行为的途径。现在，我的R35提案代表这些概念的进一步演变询问肿瘤细胞如何对细胞进行重新编程压力，包括缺氧，营养剥夺或癌症治疗。我们发现αVβ3表达可以是由压力诱导以重编程肿瘤细胞朝着耐应力的，耐药性的，类似茎状状态的诱导与肿瘤进展和转移有关的广泛癌症。因为单个肿瘤使用这种整合素以克服独特的挑战，我们将定义αVβ3如何激活下游效应在肿瘤类型，遗传特征和微环境之间。我未来研究计划的总体目标是了解这种肿瘤如何使用整联蛋白αVβ3来获得胁迫耐受性，以便我们可以设计攻击的方法这个过程理论。这项拟议的研究不仅会导致对如何肿瘤适应治疗或微环境应激，但应确定可限制的新型药物靶标通过预防或克服肿瘤细胞耐药性和胁迫耐受性来进展。