Starvation induced circulating miR-33a secretion remodeled extracellular matrix of tumor microenvironment by altering polyamine metabolism [TC TM]

Breast cancer cells secret different kinds of cargoes through extracellular vesicles (EVs) especially under stress conditions. However, the underling mechanism and function is poorly defined. Here, we found RNA binding protein ACO1 could bind miR-33a and assist their package into EVs in tumor core region. Thereby, miR-33a suppressed putrescine metabolism in cancer-associated fibroblasts (CAFs) and reprogrammed H3K4me3 mediated epigenetic regulation. Chip-seq data suggested stress granules related genes were downregulated and ECM related genes were upregulated. Most notably, putrescine inhibited KDM5C expression level but did not altered activity. Finally, our study provides a novel mechanism of how cancer EVs reprogrammed polyamine metabolism in tumor stroma, leading to spatially different distribution of ECM in tumor microenvironment. Overall design: Comparative gene expression profiling analysis of RNA-seq data for tumor core and margin established by injecting MDA-MB-231 orthotopically of NSG mice