Targeting the splicing factor hnRNP M with an endogenous circular RNA aptamer suppresses cancer metastasis

Alternative splicing (AS) is a key regulatory mechanism that expands transcriptomic diversity and is frequently hijacked by cancer cells to drive epithelial-mesenchymal transition (EMT), thereby promoting invasion and therapy resistance. However, therapeutic strategies to reprogram pathological AS networks remain limited. Here, we identified a circular RNA, MASCOT (hnRNP M-ASsociated Circular RNA Of TGFβ), that functions as an endogenous aptamer targeting the splicing factor hnRNP M, a central regulator of EMT-related AS reprogramming. As an endogenous repressor of hnRNP M, MASCOT maintains the epithelial status of cancer cells and suppresses tumor metastasis. Conversely, its downregulation by TGFβ releases hnRNP M to initiate EMT-associated splicing changes. Restoring MASCOT expression significantly reduces metastatic burden in mouse models. Mechanistically, MASCOT scaffolds hnRNP M to nucleolin within the nucleolus, spatially sequestering hnRNP M away from the spliceosome. Our findings reveal a novel regulatory circuit that controls EMT-linked splicing and identify MASCOT as a promising RNA-based therapeutic candidate against metastatic progression.