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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 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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