Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
Abstract
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 β1. Rab11b-mediated control of integrin β1 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 β1 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 15, 2020
- Source ID
- 10.1038/s41467-020-16832-2
Entities
People
- Alicia T. Lamere
- Crislyn D’souza-schorey
- Erin N Howe
- Ian H. Guldner
- James W. Clancy
- Jeremiah Zartman
- Jun Li
- Melanie E Justice
- Miranda D. Burnette
- Patricia M Schnepp
- Siyuan Zhang
- Uma K Aryal
- Victoria Hedrick
Organizations
- Indiana Clinical and Translational Sciences Institute
- National Cancer Institute
- United States Department of Defense
- United States Department of Health and Human Services