Abstract
Heterogeneity of mitochondrial activities in cancer cells exists across different disease stages and even in the same patient, with increased mitochondrial activities associated with invasive cancer phenotypes and circulating tumor cells. Here, we use a micropatterned tumor-stromal assay (μTSA) comprised of MCF-7 breast cancer cells and bone marrow stromal cells (BMSCs) as a model to investigate the role of stromal constraints in altering the mitochondrial activities of cancer cells within the tumor microenvironment (TME). Using microdissection and RNA sequencing, we revealed a differentially regulated pattern of gene expression related to mitochondrial activities and metastatic potential at the tumor-stromal interface. Gene expression was confirmed by immunostaining of mitochondrial mass, and live microscopic imaging of mitochondrial membrane potential (ΔΨm) and optical redox ratio. We demonstrated that physical constraints by the stromal cells play a major role in ΔΨm heterogeneity, which was positively associated with nuclear translocation of the YAP/TAZ transcriptional co-activators. Importantly, inhibiting actin polymerization and Rho-associated protein kinase disrupted the differential ΔΨm pattern. In addition, we showed a positive correlation between ΔΨm level and metastatic burden in vivo in mice injected with MDA-MB-231 breast cancer cells. This study supports a new regulatory role for the TME in mitochondrial heterogeneity and metastatic potential.
Highlights
The tumor microenvironment (TME) plays an important role in cancer progression and metastasis[14]
The RNA-seq data were analyzed by gene set enrichment analysis (GSEA), where statistical values were generated through the Wald Test, and gene sets www.nature.com/scientificreports were ranked by statistical significance and fold change direction
By using a micropatterned co-culture model mimicking the morphological features of early breast tumors[17,18], we show that mitochondrial and metabolic phenotypes can be spatially regulated by surrounding stromal cells under the architectural context of tumor-stromal interactions
Summary
The tumor microenvironment (TME) plays an important role in cancer progression and metastasis[14]. Not yet reported in cancer cells, it has been shown that mechanical stimuli can affect mitochondrial activity in cardiomyocytes and endothelial cells[28], and that cytoskeletal remodeling leads to changes in mitochondrial dynamics[29]. It remains unclear whether stromal cells and their associated mechanical cues within the tumor architecture can drive heterogeneous mitochondrial activities. We use the μTSA to investigate the role of stromal cells in regulating tumor mitochondrial heterogeneity in vitro. We demonstrated in the μTSA a new regulatory role that the TME plays in mitochondrial heterogeneity and metastatic potential
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