Cancer-cell-secreted miR-33a remodels extracellular matrix by targeting polyamine metabolism in stroma to promote tumorigenesis
Tumor progression depends on the bidirectional interactions between cancer and stroma in the heterogenous tumor microenvironment (TME) partially through extracellular vesicles (EVs). However, the secretary mechanism and biological effect of cancer cell derived EVs on tumor survival under starvation is poorly defined. Here, we identify cancer cells preferentially secrete miR-33a in the tumor core region with poor nutrient level. Exosomal miR-33a suppresses putrescine biosynthesis by targeting AGMAT in stromal cells, where putrescine suppresses the expression of demethylase KDM5C. Chromatin immunoprecipitation sequencing identifies miR-33a/KDM5C axis tightly regulates TIA1 gene, functioning stress granule (SG) marker. Exosomal miR-33a diminishes the assembly of stromal SGs but inducing more extracellular matrix accumulation. Collectively, our study reveals tumor selectively secretes miR-33a through EVs to remodel the stromal SG formation and extracellular matrix profiles to gain survival possibility for cancer cells under starvation, highlighting a novel regulatory mechanism of nutrient level on EV secretion and the function of polyamine metabolism in reshaping epigenetic profiles of TME. Overall design: Comparative miRNA expression profiling analysis of small RNA deep data sequencing for exosomes