期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-16832-2
关键词
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资金
- Advancing Basic Cancer Research grant from the Walther Cancer Foundation
- DOD [W81XWH-15-1-0021]
- NIH - Indiana CTSI [R01CA194697, R01CA222405, F32CA210583, R03CA212964, R01CA115316, TL1TR001107]
- Walther Cancer Foundation
- Indiana CTSI Core Pilot Fund
- Purdue Office of the Executive Vice President for Research and Partnership
Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin beta 1. Rab11b-mediated control of integrin beta 1 surface expression allows efficient engagement with the brain ECM, activating mechanotransduction signaling to promote survival. Lipophilic statins prevent membrane association and activity of Rab11b, and we provide proof-of principle that these drugs prevent breast cancer adaptation to the brain microenvironment. Our results identify Rab11b-mediated recycling of integrin beta 1 as regulating BCBM, and suggest that the recycleome, recycling-based control of the cell surface proteome, is a previously unknown driver of metastatic adaptation and outgrowth.
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