Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

Abstract

GRAPHICAL ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC=\"FIGDIR/small/666750v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (68K):\norg.highwire.dtl.DTLVardef@16dc0c4org.highwire.dtl.DTLVardef@8ab7e2org.highwire.dtl.DTLVardef@12e5acforg.highwire.dtl.DTLVardef@4bf298_HPS_FORMAT_FIGEXP M_FIG C_FIG SUMMARYBreast 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-regulate 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 {beta}1. Rab11b-mediated control of integrin {beta}1 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.\n\nManuscript SummaryRab11b up-regulation in the brain microenvironment promotes recycling of cargo proteins required for breast cancer brain metastasis, including increased surface expression of integrin {beta}1, which allows brain extracellular matrix attachment and mechanotransduction. Inhibition of the mevalonate pathway with statins prevents geranylgeranylation of Rab11b, decreasing cargo recycling, and inhibiting brain metastasis.