Elevated MPS1 converts the fibrous corona into a source of chromosomal instability in colon cancer

Pinto-Teixeira, A.; Oliveira, A.; Gouveia, G.; Sousa, A.; Roelands, J.; Grillo, M.; Rodriguez-Calado, S.; Resende, C.; Xavier-Ferreira, H.; Osswald, M.; Girao, H.; Mesquita, P.; Almeida, R.; Barisic, M.; Machado, J. C.; Sunkel, C.; van Wezel, T.; Fachinetti, D.; Szuhai, K.; de Miranda, N.; Conde, C.

doi:10.64898/2026.08.07.743489

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bioRxiv · 10.64898/2026.08.07.743489

Elevated MPS1 converts the fibrous corona into a source of chromosomal instability in colon cancer

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Abstract

Chromosomal instability (CIN), characterised by recurrent chromosome mis-segregation, fuels intratumour heterogeneity and tumour evolution. Yet, its proximal molecular causes remain ill-defined. Tumour-scale genomic and transcriptomic analyses associate MPS1 overexpression with CIN in colon carcinomas. Consistently, CIN+ patient-derived colon cancer cells (PCCCs) display elevated MPS1, frequent merotelic kinetochore-microtubule attachments and lagging chromosomes that are suppressed by partial MPS1 inhibition. Conversely, ectopic MPS1 overexpression in otherwise stable near-diploid cells phenocopies these defects, inducing micronuclei formation and karyotypic divergence. Mechanistically, MPS1 overactivity maintains ROD phosphorylation at Thr13/Ser15, continuously sustaining fibrous corona assembly despite mature end-on attachments. 3D-STED microscopy reveals split-interface configurations in which microtubules from opposing poles engage the canonical outer-kinetochore surface and a spatially distinct corona domain, explaining how merotely forms and persists into anaphase. Disrupting corona assembly restores chromosome segregation fidelity in MPS1-overexpressing RPE-1 cells and in CIN+ PCCCs. Together, our findings establish MPS1 overexpression as a driver of CIN and uncover how oncogenic transcriptional rewiring of mitotic signalling converts a transient microtubule-capture structure into a pathological source of merotely and chromosome mis-segregation in colon cancer.

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Pinto-Teixeira, A., Oliveira, A., Gouveia, G., Sousa, A., Roelands, J., Grillo, M., Rodriguez-Calado, S., Resende, C., Xavier-Ferreira, H., Osswald, M., Girao, H., Mesquita, P., Almeida, R., Barisic, M., Machado, J. C., Sunkel, C., van Wezel, T., Fachinetti, D., Szuhai, K., de Miranda, N., Conde, C.. 2026-08-11. Elevated MPS1 converts the fibrous corona into a source of chromosomal instability in colon cancer. https://doi.org/10.64898/2026.08.07.743489

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