MACC1 drives metastasis in colorectal cancer by coordinating YKT6-dependent exosome biogenesis and c-Met cargo...

Colorectal cancer metastasis remains a major cause of cancer-related mortality, with the Metastasis-Associated in Colon Cancer 1 (MACC1) protein emerging as a critical regulator of tumor progression. Although exosomes are recognized mediators of oncogenic communication, the interplay between MACC1 and exosome biology is yet to be fully explored. This study unveils a dual mechanism through which MACC1 coordinates exosome biogenesis and oncogenic cargo delivery to drive metastatic progression. We first established clinical relevance by Pearson's demonstrating a significant correlation between MACC1 expression and exosome concentration in colorectal tumors (r = 0.457, P < 0.05). Functional studies showed that MACC1-overexpressing HCT116 cells exhibited enhanced invasiveness and transmitted pro-metastatic signals via exosomes. These exosomes were significantly enriched in the c-Met oncoprotein (P < 0.05 vs. controls) and could induce epithelial-mesenchymal transition in recipient SW480 cells, significantly enhancing their migration and invasion capacities. Mechanistically, transcriptomic analysis identified several components of the exosome secretion machinery (YKT6, RAB22A, and VPS41) as downstream targets of MACC1. Promoter-binding assays confirmed that MACC1 directly activates the transcription of YKT6, a member of the Soluble N-ethylmaleimide-sensitive factor attachment protein receptor family. This protein is critical for multivesicular body-plasma membrane fusion. The transcriptional activation led to cytoplasmic accumulation of YKT6 (P < 0.05), driving a 2.9-fold increase in exosome secretion. Crucially, YKT6-mediated exosome hypersecretion facilitated the extracellular release of c-Met-enriched vesicles, establishing a feed-forward loop for metastatic propagation. Our findings delineate an integrated metastatic axis: MACC1 orchestrates (1) transcriptional upregulation of YKT6 to amplify exosome production, and (2) selective packaging of c-Met into exosomes that prime recipient cells for invasion. This dual regulatory mechanism highlights potential therapeutic targets for intercepting metastasis-specific exosome signaling in colorectal cancer.