TY - JOUR
T1 - Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
AU - Howe, Erin N.
AU - Burnette, Miranda D.
AU - Justice, Melanie E.
AU - Schnepp, Patricia M.
AU - Hedrick, Victoria
AU - Clancy, James W.
AU - Guldner, Ian H.
AU - Lamere, Alicia T.
AU - Li, Jun
AU - Aryal, Uma K.
AU - D’Souza-Schorey, Crislyn
AU - Zartman, Jeremiah J.
AU - Zhang, Siyuan
N1 - Funding Information:
This work was funded by an Advancing Basic Cancer Research grant from the Walther Cancer Foundation (S.Z. and J.J.Z.), DOD W81XWH-15-1-0021 (S.Z.) and NIH grants R01CA194697, R01CA222405 (S.Z.), F32CA210583 (E.N.H.), R03CA212964 (J.L.), R01CA115316 (C.D.S.), TL1TR001107 (E.N.H., awarded by Indiana CTSI, A. Shekhar, PI), an ENSCCII predoctoral fellowship from the Walther Cancer Foundation (P.M.S) and Indiana CTSI Core Pilot Fund (Cohort 16, S.Z. and U.K.A.). We would like to acknowledge and thank the Dee Family endowment (S.Z.). We would also like to thank members of the Zhang and D’Souza-Schorey labs for scientific insight and support. All sample preparation and LC/MS/MS analysis was performed at the Purdue Proteomics Facility. The Q Exactive Orbitrap HF mass spectrometer and the UltiMate 3000 HPLC system used for this study were purchased with generous funding from the Purdue Office of the Executive Vice President for Research and Partnership. We thank the TRiP at Harvard Medical School (NIH/NIGMS R01-GM084947) for providing transgenic RNAi fly stocks used in this study, which were obtained from the Bloomington Drosophila Stock Center (NIH P40OD018537) and the Vienna Drosophila Resource Center (VDRC, [www.vdrc.at]). We are grateful for the use of the following core facilities: Notre Dame Genomics and Bioinformatics Core Facility, Notre Dame Freimann Life Sciences Center, Indiana University School of Medicine South Bend Imaging and Flow Cytometry Core.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-16832-2
DO - 10.1038/s41467-020-16832-2
M3 - Article
C2 - 32541798
AN - SCOPUS:85086459442
SN - 2041-1723
VL - 11
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3017
ER -