Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning
Adam W. Watson,
Adam D. Grant,
Sara S. Parker,
Samantha Hill,
Michael B. Whalen,
Jayati Chakrabarti,
Michael W. Harman,
Mackenzie R. Roman,
Brittany L. Forte,
Cody C. Gowan,
Raúl Castro-Portuguez,
Lindsey K. Stolze,
Christian Franck,
Darren A. Cusanovich,
Yana Zavros,
Megha Padi,
Casey E. Romanoski,
Ghassan Mouneimne
Affiliations
Adam W. Watson
University of Arizona Cancer Center, Tucson, AZ 85724, USA; MeCo Diagnostics, Tucson, AZ 85718, USA
Adam D. Grant
University of Arizona Cancer Center, Tucson, AZ 85724, USA
Sara S. Parker
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Samantha Hill
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Michael B. Whalen
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Jayati Chakrabarti
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Michael W. Harman
School of Engineering, Brown University, Providence, RI 02912, USA
Mackenzie R. Roman
University of Arizona Cancer Center, Tucson, AZ 85724, USA
Brittany L. Forte
University of Arizona Cancer Center, Tucson, AZ 85724, USA
Cody C. Gowan
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Raúl Castro-Portuguez
University of Arizona Cancer Center, Tucson, AZ 85724, USA
Lindsey K. Stolze
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Christian Franck
Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, WI 53706, USA
Darren A. Cusanovich
Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Yana Zavros
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
Megha Padi
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; Bioinformatics Shared Resource, University of Arizona Cancer Center, Tucson, AZ 85724, USA
Casey E. Romanoski
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA; Corresponding author
Ghassan Mouneimne
University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA; Corresponding author
Summary: While the immediate and transitory response of breast cancer cells to pathological stiffness in their native microenvironment has been well explored, it remains unclear how stiffness-induced phenotypes are maintained over time after cancer cell dissemination in vivo. Here, we show that fibrotic-like matrix stiffness promotes distinct metastatic phenotypes in cancer cells, which are preserved after transition to softer microenvironments, such as bone marrow. Using differential gene expression analysis of stiffness-responsive breast cancer cells, we establish a multigenic score of mechanical conditioning (MeCo) and find that it is associated with bone metastasis in patients with breast cancer. The maintenance of mechanical conditioning is regulated by RUNX2, an osteogenic transcription factor, established driver of bone metastasis, and mitotic bookmarker that preserves chromatin accessibility at target gene loci. Using genetic and functional approaches, we demonstrate that mechanical conditioning maintenance can be simulated, repressed, or extended, with corresponding changes in bone metastatic potential.
