Attacking stress tolerance in cancer

项目摘要/摘要 我的职业生涯始于识别侵袭性细胞上的细胞表面标记，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做出反应 促进血管生成。后来我证明了肿瘤细胞上的αV整合素使用相同的基本原理 实现攻击性、侵袭性和转移性行为的途径。现在，我的R35提案代表了 这些概念的进一步演变，以询问肿瘤细胞如何经历重编程来响应细胞 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 由应激诱导，将肿瘤细胞重新编程为耐受应激、耐药、干细胞样状态，即 与多种癌症的肿瘤进展和转移有关。因为个体肿瘤使用 为了克服独特的挑战，我们将定义αvβ3如何激活不同的下游效应器 肿瘤类型、遗传特征和微环境之间的关系。我未来研究计划的总体目标是 为了了解这种肿瘤如何使用整合素αvβ3来获得应激耐受性，以便我们能够设计出攻击的方法 这一过程具有治疗性。这项拟议的研究不仅将导致对如何 肿瘤适应治疗或微环境压力，但它应该确定新的可用药靶点来限制 通过预防或克服肿瘤细胞的耐药性和应激耐受性而导致癌症的进展。

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.