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  • Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning.

Breast tumor stiffness instructs bone metastasis via maintenance of mechanical conditioning.

Cell reports (2021-07-01)
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
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-RUNX2 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Leukocyte Acid Phosphatase (TRAP) Kit, Kit formulated with all liquid reagents
Sigma-Aldrich
(-)-Blebbistatin, The active enantiomer of (±)-Blebbistatin that accounts for the inhibitory activity towards ATPase and myosin II-dependent cellular processes.
Sigma-Aldrich
CellVue® Claret Far Red Fluorescent Cell Linker Mini Kit for General Membrane Labeling, Distributed for Phanos Technologies
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid
Sigma-Aldrich
5-Aza-2′-Deoxycytidine, A cytosine analog that acts as a DNA methyltransferase inhibitor.