GSE127887
Breast tumor stiffness instructs bone metastasis via mechanical memory
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 unclear whether mechanical stimuli in the primary tumor influence distant, late-stage metastatic phenotypes in absentia. Here, we show that primary tumor stiffness promotes stable yet 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. We established a “mechanical conditioning score” comprised of mechanically-regulated genes as a proxy measurement of tumor stiffness response, and we show that it is 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. This combination of traits allows for the stable transactivation of osteolytic target genes which persists after cancer cells disseminate from their activating microenvironment. Using genetic, epigenetic, and functional approaches, RUNX2-mediated mechanical memory can be stimulated, repressed, selected, or extended. In concert with previous studies detailing how biochemical properties of the primary tumor stroma influence distinct metastatic phenotypes, the impact of local biomechanical properties we present here support a generalized model of cancer progression in which the integrated properties of the primary tumor microenvironment govern cell behavior in the metastatic microenvironment. Overall design: Two mechanical conditions were used to grow SUM159 cells: soft (0.5 kPa) and stiff (8.0 kPa) with three biological replicates.