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Breast tumor stiffness instructs bone metastasis via mechanical memory

View ORCID ProfileAdam W Watson, Adam Grant, Sara S Parker, Michael W Harman, Mackenzie R Roman, Brittany L Forte, Cody C Gowan, Raul Castro-Portuguez, Christian Franck, Darren Cusanovich, Megha Padi, Casey Romanoski, Ghassan Mouneimne
doi: https://doi.org/10.1101/847699
Adam W Watson
1 University of Arizona Cancer Center;
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Adam Grant
2 University of Arizona;
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  • For correspondence: adglink@email.arizona.edu
Sara S Parker
2 University of Arizona;
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  • For correspondence: saraparker@email.arizona.edu
Michael W Harman
3 Brown University;
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Mackenzie R Roman
2 University of Arizona;
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  • For correspondence: mroman@email.arizona.edu
Brittany L Forte
2 University of Arizona;
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  • For correspondence: bforte2012@email.arizona.edu
Cody C Gowan
2 University of Arizona;
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  • For correspondence: codygowan@email.arizona.edu
Raul Castro-Portuguez
2 University of Arizona;
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  • For correspondence: raulcastro@email.arizona.edu
Christian Franck
4 University of Wisconsin-Madison
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  • For correspondence: cfranck@wisc.edu
Darren Cusanovich
2 University of Arizona;
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  • For correspondence: darrenc@email.arizona.edu
Megha Padi
2 University of Arizona;
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  • For correspondence: mpadi@email.arizona.edu
Casey Romanoski
2 University of Arizona;
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  • For correspondence: cromanoski@email.arizona.edu
Ghassan Mouneimne
1 University of Arizona Cancer Center;
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  • For correspondence: gmouneimne@email.arizona.edu
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Abstract

The mechanical microenvironment of primary breast tumors plays a substantial role in promoting tumor progression. While the transitory response of cancer cells to pathological stiffness in their native microenvironment has been well described, it is still unclear how mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes across time and space in absentia. Here, we show that primary tumor stiffness promotes stable, non-genetically heritable phenotypes in breast cancer cells. This mechanical memory instructs cancer cells to adopt and maintain increased cytoskeletal dynamics, traction force, and 3D invasion in vitro, in addition to promoting osteolytic bone metastasis in vivo. Furthermore, we established a mechanical conditioning (MeCo) score comprised of mechanically-regulated genes as a global gene expression measurement of tumor stiffness response. Clinically, we show that a high MeCo score is strongly associated with bone metastasis in patients. Using a discovery approach, we mechanistically traced mechanical memory in part to ERK-mediated mechanotransductive activation of RUNX2, an osteogenic gene bookmarker and bone metastasis driver. The combination of these RUNX2 traits permits the stable transactivation of osteolytic target genes that remain upregulated after cancer cells disseminate from their activating microenvironment in order to modify a distant microenvironment. Using genetic, epigenetic, and functional approaches, we were able to simulate, repress, select and extend RUNX2-mediated mechanical memory and alter cancer cell behavior accordingly. In concert with previous studies detailing the influence of biochemical properties of the primary tumor stroma on distinct metastatic phenotypes, our findings detailing the influence of biomechanical properties support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern the secondary tumor microenvironment, i.e., soil instructs soil.

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Posted November 20, 2019.
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Breast tumor stiffness instructs bone metastasis via mechanical memory
Adam W Watson, Adam Grant, Sara S Parker, Michael W Harman, Mackenzie R Roman, Brittany L Forte, Cody C Gowan, Raul Castro-Portuguez, Christian Franck, Darren Cusanovich, Megha Padi, Casey Romanoski, Ghassan Mouneimne
bioRxiv 847699; doi: https://doi.org/10.1101/847699
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Breast tumor stiffness instructs bone metastasis via mechanical memory
Adam W Watson, Adam Grant, Sara S Parker, Michael W Harman, Mackenzie R Roman, Brittany L Forte, Cody C Gowan, Raul Castro-Portuguez, Christian Franck, Darren Cusanovich, Megha Padi, Casey Romanoski, Ghassan Mouneimne
bioRxiv 847699; doi: https://doi.org/10.1101/847699

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