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Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth

View ORCID ProfileErin 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, View ORCID ProfileCrislyn D’Souza-Schorey, View ORCID ProfileJeremiah Z. Zartman, View ORCID ProfileSiyuan Zhang
doi: https://doi.org/10.1101/666750
Erin N. Howe
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
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Miranda D. Burnette
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
3Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, USA
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Melanie E. Justice
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
4Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA
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James W. Clancy
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
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Ian H. Guldner
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
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Patricia M. Schnepp
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
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Victoria Hendrick
5Purdue Proteomics Facility, Bindley Bioscience Center, Discovery Park, Purdue University, West Lafayette, IN, USA
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Uma K. Aryal
5Purdue Proteomics Facility, Bindley Bioscience Center, Discovery Park, Purdue University, West Lafayette, IN, USA
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Alicia T. Specht
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
6Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA
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Jun Li
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
6Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA
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Crislyn D’Souza-Schorey
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
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Jeremiah Z. Zartman
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
3Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN, USA
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Siyuan Zhang
1Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
2Mike and Josie Harper Cancer Research Institute, University of Notre Dame, 1234 N. Notre Dame Avenue, South Bend, IN, USA
7Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA
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  • For correspondence: szhang8@nd.edu
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SUMMARY 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-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 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.

Manuscript Summary Rab11b up-regulation in the brain microenvironment promotes recycling of cargo proteins required for breast cancer brain metastasis, including increased surface expression of integrin β1, 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.

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  • Declaration of Conflict of Interest: The authors declare no competing interests.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted June 11, 2019.
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Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
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 Z. Zartman, Siyuan Zhang
bioRxiv 666750; doi: https://doi.org/10.1101/666750
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Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth
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 Z. Zartman, Siyuan Zhang
bioRxiv 666750; doi: https://doi.org/10.1101/666750

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