βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer

Kokkinos, J.; Sharbeen, G.; Ignacio, R. M. C.; Pandzic, E.; Youkhana, J.; Boyer, C.; Haghighi, K. S.; Gunawarman, M.; Goldstein, D.; Gebski, V.; Pajic, M.; Pitiyarachchi, O.; Davis, M. E.; Schulstad, G.; Arkell, O. S. M.; Kopecky, C.; Gonzales-Aloy, E.; Erkan, M.; Morton, J. P.; Kavallaris, M.; Gunning, P. W.; Hardeman, E. C.; Johns, A.; Gill, A. J.; Whan, R. M.; Mawson, A.; Australian Pancreatic Cancer Genome Initiative,; McCarroll, J. A.; Phillips, P. A.

doi:10.1101/2022.09.29.510034

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bioRxiv · 10.1101/2022.09.29.510034

βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer

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Abstract

The microtubule protein, {beta}III-tubulin, has been implicated as a prognostic, pro-survival, and chemoresistance factor in some of the most lethal malignancies including pancreatic ductal adenocarcinoma (PDAC). However, precise survival mechanisms controlled by {beta}III-tubulin in cancer cells are unknown. Here, we report an unexpected role of {beta}III-tubulin as a brake on extrinsic caspase 8-dependent apoptosis in PDAC. We show that {beta}III-tubulin knockdown frees death-receptor DR5 to increase its membrane diffusion, clustering, and activation of cell-death. We demonstrate that {beta}III-ubulin silencing increases sensitivity of PDAC cells to chemotherapeutic and microenvironment-derived extrinsic cell-death signals including TRAIL, TNF, and FasL. Finally, nanoparticle delivery of {beta}III-tubulin siRNA to mouse orthotopic PDAC tumours in vivo and human patient-derived PDAC tumour explants ex vivo increases extrinsic apoptosis and reduces tumour progression. Thus, silencing of {beta}III-tubulin represents an innovative strategy to unleash a suicide signal in PDAC cells and render them sensitive to microenvironment and chemotherapy-derived death signals.

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Kokkinos, J., Sharbeen, G., Ignacio, R. M. C., Pandzic, E., Youkhana, J., Boyer, C., Haghighi, K. S., Gunawarman, M., Goldstein, D., Gebski, V., Pajic, M., Pitiyarachchi, O., Davis, M. E., Schulstad, G., Arkell, O. S. M., Kopecky, C., Gonzales-Aloy, E., Erkan, M., Morton, J. P., Kavallaris, M., Gunning, P. W., Hardeman, E. C., Johns, A., Gill, A. J., Whan, R. M., Mawson, A., Australian Pancreatic Cancer Genome Initiative,, McCarroll, J. A., Phillips, P. A.. 2022-10-01. βIII-Tubulin is a Brake on Extrinsic Cell-Death in Pancreatic Cancer. https://doi.org/10.1101/2022.09.29.510034

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