Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

Erin N. Howe, Miranda D. Burnette, Melanie E. Justice, Patricia M. Schnepp, Victoria Hedrick, James W. Clancy, Ian H. Guldner, Alicia T. Lamere, Jun Li, Uma K. Aryal, Crislyn D’Souza-Schorey, Jeremiah J. Zartman, Siyuan Zhang

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Article number3017
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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