Iron reshapes polyamine metabolism through controlling exosomal miR-33a secretion to remodel extracellular matrix in tumor microenvironment

Tumor progression depends on the bidirectional interactions between cancer and stroma in the heterogenous tumor microenvironment (TME) partially through extracellular vesicles (EVs). However, the secretion mechanism and biological effect of cancer cell-derived EVs on tumor survival under starvation is poorly defined. Here, we demonstrate cancer cells selectively secrete miR-33a with the assistance of protein ACO1 under glucose starvation and lower iron level, which affiliates the binding capability of miR-33a and ACO1. Exosomal miR-33 suppresses putrescine biosynthesis by targeting AGMAT in tumor stroma, where putrescine inhibits the expression of demethylase KDM5C. TIA1 gene, stress granule (SG) marker, is tightly regulated by miR-33a/KDM5C axis. Exosomal miR-33a diminishes the formation of SGs in tumor stroma but inducing more fibronectin secretion into TME. Collectively, our study reveals tumor secrets distinct EV cargoes to remodel the SGs and extracellular matrix of TME to gain survival possibility, highlighting a novel regulatory mechanism of iron and nutrient level on EV secretion in TME.