Attacking stress tolerance in cancer

攻击癌症的压力耐受性

• 批准号: 10685400
• 负责人: DAVID A CHERESH
• 金额: $ 88.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10685400
• 关键词: Antineoplastic Agents; Basic Cancer Research; Behavior; Cell Surface Receptors; Cell Survival; Cell surface; Cells; Cellular Stress; Cues; Drug resistance; Endothelial Cells; Evolution; FDA approved; Genetic; Goals; Hypoxia; Individual; Integrin alphaV; Integrin alphaVbeta3; Integrins; Lead; Malignant Neoplasms; Mediating; Neoplasm Metastasis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiological; Process; Research; Stress; Supporting Cell; Therapeutic; angiogenesis; cancer therapy; career; neoplastic cell; new therapeutic target; nutrient deprivation; phase III trial; prevent; programs; response; stem; stress tolerance; translational cancer research; tumor; tumor microenvironment; tumor progression

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.

项目总结/文摘

项目成果

Metastasis is a highly stressful process.

• DOI: 10.1007/s10555-020-09938-y
• 发表时间: 2020-12
• 期刊: Cancer metastasis reviews
• 作者: Campos AD;Weis SM;Cheresh DA
• 通讯作者: Cheresh DA