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Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

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

Posted 11 Jun 2019
bioRxiv DOI: 10.1101/666750

Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for up to 30% of mortality. Developing new therapeutics requires a molecular understanding of adaptation to the brain microenvironment. Here, we combined RNA-sequencing of BCBM development with a reverse genetic screen in Drosophila melanogaster and identified Rab11b, an endosomal recycling protein, as a mediator of metastatic adaptation. We show that disseminated cells up-regulated Rab11b early after arrival in the brain, allowing control of the cell surface proteome through recycling of proteins required for successful interaction with the microenvironment, including integrin β1. Rab11b-mediated control of integrin β1 surface expression allows ligation to the brain ECM, activating mechanotransduction signaling to allow survival and proliferation. We propose a model in which up-regulation of Rab11b allows disseminated cells to recycle needed proteins during metastatic adaptation, without strictly requiring transcription and translation, to allow for metastatic outgrowth.

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