Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

Dunbar, K.; Valanciute, A.; Rajasekaran, V.; Jamieson, T.; Freile Vinuela, P.; Lima, A.; Blackmur, J.; Ochocka-Fox, A.-M.; Arends, M. J.; Sansom, O. J.; Myant, K. B.; Farrington, S. M.; Dunlop, M. G.; Din, F. V. N.

doi:10.1101/809517

bioRxiv · 10.1101/809517

Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids

Dunbar, K.·Valanciute, A.·Rajasekaran, V.·Jamieson, T.·Freile Vinuela, P.·Lima, A.·Blackmur, J.·Ochocka-Fox, A.-M.·Arends, M. J.·Sansom, O. J.·Myant, K. B.·Farrington, S. M.·Dunlop, M. G.·Din, F. V. N.

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Abstract

Aspirin reduces the incidence and mortality of colorectal cancer (CRC). Wnt signalling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations (CSC). Here, we investigated whether aspirin can rescue these pro-invasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 (DKK-1) in CRC cells and organoids derived from FAP patients. We provide evidence of phenotypic biomarkers of aspirin response with an increased epithelial and reduced stem-like state mediated by an increase in DKK-1. Thus we highlight a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.

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Dunbar, K., Valanciute, A., Rajasekaran, V., Jamieson, T., Freile Vinuela, P., Lima, A., Blackmur, J., Ochocka-Fox, A.-M., Arends, M. J., Sansom, O. J., Myant, K. B., Farrington, S. M., Dunlop, M. G., Din, F. V. N.. 2019-10-17. Aspirin-mediated DKK-1 increase rescues Wnt-driven stem-like phenotype in human intestinal organoids. https://doi.org/10.1101/809517

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