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Breast tumor stiffness instructs bone metastasis via mechanical memory

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 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE127887 | GEO | 2021/07/01

REPOSITORIES: GEO

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Project description:Previously, we have identified the RUNX2 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared to primary cultures derived from matched primary (prior to CT) tumors. However, we found no differences in the RUNX2 methylation in primary EOC tumors and EOC omental metastases, suggesting that DNA methylation-based epigenetic mechanisms have no impact on RUNX2 expression in advanced (metastatic) stage of the disease. Moreover, RUNX2 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. Knockdown of the RUNX2 expression in EOC cells led to sharp decrease of cell proliferation and significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as various genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX2 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX2 gene in EOC progression and suggest that RUNX2 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX2 and other members of the RUNX gene family in ovarian tumorigenesis. To better understand the molecular mechanisms of RUNX2 gene action in ovarian cancer cells, we employed the Agilent Whole Human Genome microarrays, containing ~ 44,000 genes to identify global gene expression changes upon RUNX2 suppression in SKOV3 cells. We compared the gene expression of the previously selected clone shRNA- RUNX2-knockdown clone 3 (cl3) against the corresponding control clone. The microarray experiments were performed in duplicates, as two hybridizations were carried out for the RUNX2-suppressing cell clone against the corresponding control, using a fluorescent dye reversal (dye-swap) technique.

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Breast tumor stiffness instructs bone metastasis via mechanical memory

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