Attacking stress tolerance in cancer

项目概要/摘要 我的职业生涯开始于鉴定侵入性细胞的细胞表面标记，并导致了 内皮细胞上的整合素αvβ3和αvβ5如何对肿瘤微环境中的信号作出反应， 促进血管生成。我后来证明，肿瘤细胞上的αV整合素使用这些相同的基本原理， 途径来实现侵略性、侵入性和转移性行为。现在，我的R35提案代表了一个 这些概念的进一步发展，以询问肿瘤细胞如何响应细胞凋亡而进行重编程。 压力，包括缺氧、营养缺乏或癌症治疗。我们发现αvβ3的表达可以是 通过应激诱导肿瘤细胞向应激耐受、耐药、干细胞样状态重新编程， 与多种癌症的肿瘤进展和转移相关。因为个体肿瘤利用 为了克服这种独特的挑战，我们将定义αvβ3如何激活下游效应子， 肿瘤类型遗传特征和微环境之间的联系我未来研究计划的总体目标是 为了了解这些肿瘤如何利用整合素αvβ3获得应激耐受性， 这个治疗过程。这项拟议中的研究不仅将导致对如何从根本上理解 肿瘤适应治疗或微环境压力，但它应该确定新的药物靶点，以限制 通过预防或克服肿瘤细胞的耐药性和应激耐受性来促进癌症进展。

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.