Cancer-associated MORC2 mutant M276I regulates an hnRNPM-mediated CD44 splicing switch to promote invasion and metastasis in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with a high propensity for distant metastasis and limited treatment options, yet its molecular underpinnings remain largely unknown. Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein whose mutations have been causally implicated in several neurological disorders. Here we report that a cancer-associated substitution of methionine to isoleucine at residue 276 (M276I) of MORC2 confers gain-of-function properties in the metastatic progression of TNBC. Expression of mutant MORC2 in TNBC cells increased cell migration, invasion, and lung metastasis without affecting cell proliferation and primary tumor growth compared with its wild-type counterpart. The M276I mutation enhanced binding of MORC2 to heterogeneous nuclear ribonucleoprotein M (hnRNPM), a component of the spliceosome machinery. This interaction promoted an hnRNPM-mediated splicing switch of CD44 from the epithelial isoform (CD44v) to the mesenchymal isoform (CD44s), ultimately driving epithelial-mesenchymal transition (EMT). Knockdown of hnRNPM reduced the binding of mutant MORC2 to CD44 pre-mRNA and reversed the mutant MORC2-induced CD44 splicing switch and EMT, consequently impairing the migratory, invasive, and lung metastatic potential of mutant MORC2-expressing cells. Collectively, these findings provide the first functional evidence for the M276I mutation in promoting TNBC progression. They also establish the first mechanistic connection between MORC2 and RNA splicing and highlight the importance of deciphering unique patient-derived mutations for optimizing clinical outcomes of this highly heterogeneous disease.

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