In BRAFV600E-mutated colorectal cancer cells, fascin1 restructures adherens junctions to drive Wnt activation

Pham, E.; Esmaeilniakooshkghazi, A.; George, S. P.; Ahrorov, A.; Villagomez, F. R.; Byington, M.; Mukhopadhyay, S.; Patnaik, S.; Conrad, J. C.; Naik, M.; Ravi, S.; Tebbuttt, N.; Mooi, J.; Reehorst, C. M.; Mariadason, J. M.; Khurana, S.

doi:10.1101/2022.06.14.496198

bioRxiv · 10.1101/2022.06.14.496198

In BRAFV600E-mutated colorectal cancer cells, fascin1 restructures adherens junctions to drive Wnt activation

Pham, E.·Esmaeilniakooshkghazi, A.·George, S. P.·Ahrorov, A.·Villagomez, F. R.·Byington, M.·Mukhopadhyay, S.·Patnaik, S.·Conrad, J. C.·Naik, M.·Ravi, S.·Tebbuttt, N.·Mooi, J.·Reehorst, C. M.·Mariadason, J. M.·Khurana, S.

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Abstract

Fascin1 expression in colorectal carcinomas (CRCs) is linked to a clinically aggressive disease with poor prognosis. Despite that fascin1s role in the etiology of CRCs has not been directly investigated. We show fascin1 expression in one-third of all CRCs underscoring the critical need to identify fascin1s function in colorectal carcinogenesis. Here, we identify for the first time, fascin1s role as a mechanosensor that modulates CRC cell adherens junction (AJ) plasticity to induce tumor growth and metastasis. We show that fascin1 expression drives protein sorting to transform AJ mechanotransduction and we reveal how these force-sensitive pathways activate oncogenic signaling in CRC cells. We made the novel finding that AJ remodeling by fascin1 also controls "collective plasticity" and bidirectional cell migration. Few studies have examined AJ plasticity in cancer cells, which remains poorly understood and has not been therapeutically targeted. Our findings could have widespread implications for understanding and treating metastatic carcinomas.

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Pham, E., Esmaeilniakooshkghazi, A., George, S. P., Ahrorov, A., Villagomez, F. R., Byington, M., Mukhopadhyay, S., Patnaik, S., Conrad, J. C., Naik, M., Ravi, S., Tebbuttt, N., Mooi, J., Reehorst, C. M., Mariadason, J. M., Khurana, S.. 2022-06-17. In BRAFV600E-mutated colorectal cancer cells, fascin1 restructures adherens junctions to drive Wnt activation. https://doi.org/10.1101/2022.06.14.496198

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