Abstract
The microtubule protein βIII-tubulin is a prognostic, pro-survival, and chemoresistance factor in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the precise survival mechanisms controlled by βIII-tubulin in cancer remain unknown. Here, we discovered a link between βIII-tubulin and the activation of caspase 8-mediated extrinsic apoptosis. Silencing βIII-tubulin in PDAC cells activated caspase 8, leading to decreased cell viability and growth both in vitro and in vivo. βIII-tubulin knockdown also increased the sensitivity of PDAC cells to extrinsic cell death signals, including TNF-related apoptosis-inducing ligand (TRAIL), TNFα, and FasL. Furthermore, we demonstrated that βIII-tubulin knockdown in PDAC cells, in the absence or presence of TRAIL, increased diffusion and clustering of the TRAIL death receptor DR5 at the cell membrane, inducing extrinsic apoptosis. Nanoparticle delivery of βIII-tubulin siRNA to mouse PDAC tumours reduced tumour growth and increased responsiveness to TRAIL therapy. In patient-derived human PDAC explants, βIII-tubulin silencing reduced tumour cell frequency and improved sensitivity to TRAIL. Finally, we showed that high βIII-tubulin expression in the human PDAC stroma was independently prognostic for poor overall survival. Taken together, silencing βIII-tubulin represents an innovative strategy to activate a suicide signal in PDAC cells and render them more sensitive to microenvironment- and chemotherapy-derived death signals.
Similar content being viewed by others
Acknowledgements
Biospecimens and data used for tumour explants were obtained from the Health Precincts Biobank, UNSW Biorepository, UNSW Sydney, Australia. We sincerely thank the patients who consented to donate their tumour samples for research. We would like to thank Dr. Carmel Quinn and Dr. Anusha Hettiaratchi of the Health Precincts Biobank for their support in managing clinical samples and patient consent. We would also like to acknowledge our community consumers Gino Iori, Michelle Daly, and Claire Harvey for their invaluable input on the project and grant applications. Biospecimens and clinical data for prognostic studies were provided by the Avner APGI Bioresource (www.pancreaticcancer.net.au), which is supported by PanKind, The Australian Pancreatic Cancer Foundation (www.pankind.org.au). We acknowledge the Flow Cytometry, Katharina Gaus Light Microscopy Facility, and Biological Resource Imaging Facility within the Mark Wainwright Analytical Centre at UNSW Sydney for their technical support. In Memoriam: This work is dedicated to the memory of A/Professor Joshua McCarroll (23/4/1973–13/5/2025), a valued colleague, co-author, and beloved husband to senior author, Professor Phoebe Phillips. Joshua’s scientific insights, unwavering commitment, and collaborative spirit were instrumental in advancing this research on βIII-tubulin and pancreatic cancer. His passion for knowledge and improving outcomes for patients will continue to inspire our work. We honour his life and contributions to science with deep gratitude.
Funding
National Health and Medical Research Council Ideas Grant (Phillips, Sharbeen, APP2002707); NHMRC project grant (Phillips, McCarroll, Goldstein, APP1144108); Tour de Cure Senior Research Grant (Phillips, McCarroll, Goldstein, RSP-235-2020); Tour de Cure Pioneering Research Grant (Sharbeen, Phillips, Goldstein, RSP-255-2020); Cancer Institute NSW Translational Program Grant (Phillips, Goldstein, 2020/TPG2100); Tour de Cure PhD Support Scholarship (Kokkinos, Phillips, Goldstein, RSP-011-18/19); Cancer Research UK Institute Award (Morton, A29996); Australian Government Research Training Program Scholarship and UNSW Sydney Scientia PhD Scholarship (Kokkinos); Cancer-Institute NSW Career Development Fellowship (Sharbeen, CDF181166); Maridulu Budyari Gumal Sydney Partnership for Health, Education, Research and Enterprise [SPHERE] Cancer Clinical Academic Group Senior Research Fellowship (Funded by Cancer Institute NSW Translational Cancer Research Capacity Building Grant, 2021/CBG0003, Sharbeen); NSW Health Advanced Therapeutics Impact Grant (Sharbeen, Phillips, McCarroll, Haghighi, Goldstein); Avner Pancreatic Cancer Foundation Innovation Grant (Phillips, McCarroll, Goldstein, and Sharbeen, APCF0050618); Cancer-Institute NSW ECF (Sharbeen, 13/ECF/1–to08); Cancer Institute NSW Translational Program Grant (2020/TPG2100; Goldstein, Phillips, Pajic), NSW Health Advanced Therapeutics Impact Grant (Sharbeen, Phillips, Goldstein, McCarroll); Olivia Lambert Foundation (McCarroll), and Cancer Australia (Phillips, McCarroll and Goldstein, APP1126736); Philanthropic support from Mr Paul Dainty, Dr Marjorie O’Neil, Dr Keri Spooner, and the Ippolito family: Ignazia, Ilana and Stefan.
Author information
Authors and Affiliations
Consortia
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Edited by Dr Andre Samson
In memoriam
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Sharbeen, G., Kokkinos, J., Schulstad, G. et al. βIII-tubulin can act as a brake on extrinsic apoptosis in pancreatic cancer. Cell Death Dis (2026). https://doi.org/10.1038/s41419-026-08657-6
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41419-026-08657-6
