Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Reisenauer, K. N.; Tao, Y.; Song, S.; Patel, S.; Ingros, A.; Sheesley, P.; Masi, M.; Boari, A.; Taube, J. H.; Evidente, A.; Kornienko, A.; Romo, D.

doi:10.1101/2020.05.06.079343

bioRxiv · 10.1101/2020.05.06.079343

Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A

Reisenauer, K. N.·Tao, Y.·Song, S.·Patel, S.·Ingros, A.·Sheesley, P.·Masi, M.·Boari, A.·Taube, J. H.·Evidente, A.·Kornienko, A.·Romo, D.

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Abstract

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapy, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover, prolonged, sub-cytotoxic exposure to OpA is sufficient to reduce migration, sphere formation, and resistance to doxorubicin. OpA is well-tolerated in mice and treatment with OpA alone reduces tumor burden. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

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Reisenauer, K. N., Tao, Y., Song, S., Patel, S., Ingros, A., Sheesley, P., Masi, M., Boari, A., Taube, J. H., Evidente, A., Kornienko, A., Romo, D.. 2020-05-08. Epithelial-mesenchymal transition sensitizes breast cancer cells to cell death via the fungus-derived sesterterpenoid ophiobolin A. https://doi.org/10.1101/2020.05.06.079343

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