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.
Highlights
Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; mechanisms governing adaptation to the brain microenvironment remain poorly defined
We found that the 40 dpi brain metastases clustered away from 7 dpi samples, regardless of the size at dissection (Supplementary Fig. 1c), suggesting that metastatic adaptation and acquisition of a proliferative phenotype directs transcriptional reprogramming
We provide here two significant insights into breast cancer brain metastasis
Summary
Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; mechanisms governing adaptation to the brain microenvironment remain poorly defined. We identify Rab11b-mediated endosomal recycling as a unique mechanism for cancer cell adaptation to a challenging brain metastatic microenvironment. We first identify differentially regulated genes by utilizing RNA-sequencing to identify temporal changes during BCBM development We screen those genes for a functional role in brain metastasis using a Drosophila melanogaster tumor model[18], leading to the identification of Rab11b, a mediator of endosomal recycling. We find that breast cancer cells up-regulate Rab11b during early adaptation to the brain metastatic site, providing a mechanism for DTCs to recycle needed proteins during this critical step of the metastatic cascade, enabling survival and outgrowth. Rab11b-mediated control of the cell-surface proteome, including recycling of integrin β1, enables successful interaction with the brain ECM and mechanotransduction-activated survival signaling. Our findings suggest recycling controls the composition of the cell-surface proteome, which is critically important for metastatic cell-microenvironmental interaction and eventual outgrowth
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