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Cancer-cell-secreted miR-33a remodels extracellular matrix by targeting polyamine metabolism in stroma to promote tumorigenesis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275167 | GEO | 2025/08/19

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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Cancer-cell-secreted miR-33a remodels extracellular matrix by targeting polyamine metabolism in stroma to promote tumorigenesis

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