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Aurora Kinase A and B inhibition abrogates ‘Neosis’, a non-mitotic cell division of GBM residual cells and prevents GBM recurrence

Oncogene volume 44, pages 2103–2115 (2025)Cite this article

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Abstract

Glioblastoma (GBM) has a dismal median survival of 15 months owing to therapy resistance and inevitable recurrence. Using our cellular models of GBM radiation resistance, we had shown that GBM recurrence is due to survival and proliferation of residual disease cells enriched in multinucleated giant cells (MNGCs). However, MNGC division mechanism remained elusive. Here, using live-cell imaging we found daughter cells emerge from MNGCs by cytoplasmic pinching. Lack of DNA condensation, absence of spindle poles and acto-myosin contractile ring in dividing-MNGCs confirmed non-mitotic division of MNGCs. Furthermore, MNGCs harboured DNA damage, senescence phenotype, repeated atypical division after radiation exposure, characteristics of unconventional division called ‘Neosis’. Molecularly, WGCNA co-expression network analysis of RNA-Sequencing from parent, non-dividing MNGCs and dividing-MNGCs identified significantly high expression of aurora kinases (AurA and AurB) specifically in dividing-MNGCs. Pharmacological and genetic inhibition of aurora kinases abrogated MNGC neosis, preventing GBM recurrence in vitro and in vivo in an orthotopic GBM mouse model. Together, this study demonstrates that MNGCs divide by neosis, an atypical division mediated by AurA and AurB and identify aurora kinases as a potential molecular target to inhibit neosis and prevent GBM recurrence.

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Fig. 1: Characterization of irradiation-induced residual cells generated from in vitro radiation survival models.
Fig. 2: MNGCs do not exhibit conventional mitotic and cytokinetic features during cell division.
Fig. 3: MNGCs repopulate tumor via neosis.
Fig. 4: AurA and AurB are the candidates involved in MNGC neosis.
Fig. 5: Pharmacological and genetic inhibition of aurora kinases abrogate parent mitosis and MNGC neosis both in vitro and in vivo.

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Data availability

The RNA sequencing data analyzed for the current study are available in the EMBL-EBI ArrayExpress repository under accession number E-MTAB-14162. Please note that part of the above data is also available under accession number E-MTAB-13786 as it was re-analysed for the current study independently. Data will be available on reasonable request.

References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  2. Osuka S, Van Meir EG. Overcoming therapeutic resistance in glioblastoma: the way forward. J Clin Investig. 2017;127:415–26.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kaur E, Rajendra J, Jadhav S, Shridhar E, Goda JS, Moiyadi A, et al. Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence. Carcinogenesis. 2015;36:685–95.

    Article  CAS  PubMed  Google Scholar 

  4. Kaur E, Sahu A, Hole AR, Rajendra J, Chaubal R, Gardi N, et al. Unique spectral markers discern recurrent Glioblastoma cells from heterogeneous parent population. Scientific Rep. 2016;6:26538.

    Article  CAS  Google Scholar 

  5. Kaur E, Goda JS, Ghorai A, Salunkhe S, Shetty P, Moiyadi AV, et al. Molecular features unique to glioblastoma radiation resistant residual cells may affect patient outcome - a short report. Cell Oncol. 2019;42:107–16.

    Article  CAS  Google Scholar 

  6. Rajendra J, Datta KK, Ud Din Farooqee SB, Thorat R, Kumar K, Gardi N, et al. Enhanced proteasomal activity is essential for long term survival and recurrence of innately radiation resistant residual glioblastoma cells. Oncotarget. 2018;9:27667–81.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Zhang S, Mercado-Uribe I, Xing Z, Sun B, Kuang J, Liu J. Generation of cancer stem-like cells through the formation of polyploid giant cancer cells. Oncogene. 2014;33:116–28.

    Article  CAS  PubMed  Google Scholar 

  8. Lv H, Shi Y, Zhang L, Zhang D, Liu G, Yang Z, et al. Polyploid giant cancer cells with budding and the expression of cyclin E, S-phase kinase-associated protein 2, stathmin associated with the grading and metastasis in serous ovarian tumor. BMC Cancer. 2014;14:576.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fei F, Zhang D, Yang Z, Wang S, Wang X, Wu Z, et al. The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J Exp Clin Cancer Res. 2015;34:158.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zhang S, Zhang D, Yang Z, Zhang X. Tumor budding, micropapillary pattern, and polyploidy giant cancer cells in colorectal cancer: current status and future prospects. Stem Cells Int. 2016;2016:4810734.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mittal K, Donthamsetty S, Kaur R, Yang C, Gupta MV, Reid MD, et al. Multinucleated polyploidy drives resistance to Docetaxel chemotherapy in prostate cancer. Br J Cancer. 2017;116:1186–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu Y, Shi Y, Wu M, Liu J, Wu H, Xu C, et al. Hypoxia-induced polypoid giant cancer cells in glioma promote the transformation of tumor-associated macrophages to a tumor-supportive phenotype. CNS Neurosci Ther. 2022;28:1326–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alhaddad L, Chuprov-Netochin R, Pustovalova M, Osipov AN, Leonov S. Polyploid/multinucleated giant and slow-cycling cancer cell enrichment in response to X-ray irradiation of human glioblastoma multiforme cells differing in radioresistance and TP53/PTEN status. Int J Mol Sci. 2023;24:1228.

  14. Mansilla S, Priebe W, Portugal J. Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle. 2006;5:53–60.

    Article  CAS  PubMed  Google Scholar 

  15. Eom Y-W, Kim MA, Park SS, Goo MJ, Kwon HJ, Sohn S, et al. Two distinct modes of cell death induced by doxorubicin: apoptosis and cell death through mitotic catastrophe accompanied by senescence-like phenotype. Oncogene. 2005;24:4765–77.

    Article  CAS  PubMed  Google Scholar 

  16. Puig PE, Guilly MN, Bouchot A, Droin N, Cathelin D, Bouyer F, et al. Tumor cells can escape DNA-damaging cisplatin through DNA endoreduplication and reversible polyploidy. Cell Biol Int. 2008;32:1031–43.

    Article  CAS  PubMed  Google Scholar 

  17. Mansilla S, Bataller M, Portugal J. A nuclear budding mechanism in transiently arrested cells generates drug-sensitive and drug-resistant cells. Biochem Pharm. 2009;78:123–32.

    Article  CAS  PubMed  Google Scholar 

  18. Weihua Z, Lin Q, Ramoth AJ, Fan D, Fidler IJ. Formation of solid tumors by a single multinucleated cancer cell. Cancer. 2011;117:4092–9.

    Article  PubMed  Google Scholar 

  19. Nair J, Basha Syed S, Mahaddalkar T, Ketkar M, Thorat R, Sastri Goda J, et al. DUSP6 regulates radiosensitivity in glioblastoma by modulating the recruitment of phosphorylated DNAPKcs at DNA double-strand breaks. J Cell Sci. 2021;134:jcs259520.

  20. Kaur E, Nair J, Ghorai A, Mishra SV, Achareker A, Ketkar M, et al. Inhibition of SETMAR-H3K36me2-NHEJ repair axis in residual disease cells prevents glioblastoma recurrence. Neuro Oncol. 2020;22:1785–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ghorai A, Mahaddalkar T, Thorat R, Dutt S. Sustained inhibition of PARP-1 activity delays glioblastoma recurrence by enhancing radiation-induced senescence. Cancer Lett. 2020;490:44–53.

    Article  CAS  PubMed  Google Scholar 

  22. White-Gilbertson S, Lu P, Norris JS, Voelkel-Johnson C. Genetic and pharmacological inhibition of acid ceramidase prevents asymmetric cell division by neosis. J Lipid Res. 2019;60:1225–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559.

    Article  Google Scholar 

  24. Charan J, Kantharia ND. How to calculate sample size in animal studies?. J Pharm Pharmacother. 2013;4:303–6.

    Article  Google Scholar 

  25. Festing MFW, Altman DG. Guidelines for the design and statistical analysis of experiments using laboratory animals. ILAR J. 2002;43:244–58.

    Article  CAS  PubMed  Google Scholar 

  26. Festing MF. Design and statistical methods in studies using animal models of development. Ilar J. 2006;47:5–14.

    Article  CAS  PubMed  Google Scholar 

  27. Berul CI, Aronovitz MJ, Wang PJ, Mendelsohn ME. In vivo cardiac electrophysiology studies in the mouse. Circulation. 1996;94:2641–8.

    Article  CAS  PubMed  Google Scholar 

  28. Zheng C, Snow BE, Elia AJ, Nechanitzky R, Dominguez-Brauer C, Liu S, et al. Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma. Nat Cancer. 2023;4:1437–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Rakhmilevich AL, Felder M, Lever L, Slowinski J, Rasmussen K, Hoefges A, et al. Effective combination of innate and adaptive immunotherapeutic approaches in a mouse melanoma model. J Immunol. 2017;198:1575–84.

    Article  CAS  PubMed  Google Scholar 

  30. Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: mitotic catastrophe. Cell Death Differ. 2008;15:1153–62.

    Article  CAS  PubMed  Google Scholar 

  31. Heald R, Tournebize R, Blank T, Sandaltzopoulos R, Becker P, Hyman A, et al. Self-organization of microtubules into bipolar spindles around artificial chromosomes in Xenopus egg extracts. Nature. 1996;382:420–5.

    Article  CAS  PubMed  Google Scholar 

  32. Nunes V, Dantas M, Castro D, Vitiello E, Wang I, Carpi N, et al. Centrosome–nuclear axis repositioning drives the assembly of a bipolar spindle scaffold to ensure mitotic fidelity. Mol Biol Cell. 2020;31:1675–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Doxsey SJ, Stein P, Evans L, Calarco PD, Kirschner M. Pericentrin, a highly conserved centrosome protein involved in microtubule organization. Cell. 1994;76:639–50.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang Z, Feng X, Deng Z, Cheng J, Wang Y, Zhao M, et al. Irradiation-induced polyploid giant cancer cells are involved in tumor cell repopulation via neosis. Mol Oncol. 2021;15:2219–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rajaraman R, Rajaraman MM, Rajaraman SR, Guernsey DL. Neosis–a paradigm of self-renewal in cancer. Cell Biol Int. 2005;29:1084–97.

    Article  CAS  PubMed  Google Scholar 

  36. Gupta A, Hunt CR, Chakraborty S, Pandita RK, Yordy J, Ramnarain DB, et al. Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res. 2014;181:1–8.

    Article  CAS  PubMed  Google Scholar 

  37. Diaz RJ, Golbourn B, Faria C, Picard D, Shih D, Raynaud D, et al. Mechanism of action and therapeutic efficacy of Aurora kinase B inhibition in MYC overexpressing medulloblastoma. Oncotarget. 2015;6:3359–74.

    Article  PubMed  Google Scholar 

  38. Gully CP, Zhang F, Chen J, Yeung JA, Velazquez-Torres G, Wang E, et al. Antineoplastic effects of an Aurora B kinase inhibitor in breast cancer. Mol Cancer. 2010;9:42.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Willems E, Dedobbeleer M, Digregorio M, Lombard A, Lumapat PN, Rogister B. The functional diversity of Aurora kinases: a comprehensive review. Cell Div. 2018;13:7.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Adibi R, Moein S, Gheisari Y. Zoledronic acid targets chemo-resistant polyploid giant cancer cells. Sci Rep. 2023;13:419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rajaraman R, Guernsey DL, Rajaraman MM, Rajaraman SR. Stem cells, senescence, neosis and self-renewal in cancer. Cancer Cell Int. 2006;6:25.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Kanada M, Nagasaki A, Uyeda TQ. Adhesion-dependent and contractile ring-independent equatorial furrowing during cytokinesis in mammalian cells. Mol Biol Cell. 2005;16:3865–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sundaram M, Guernsey DL, Rajaraman MM, Rajaraman R. Neosis: a novel type of cell division in cancer. Cancer Biol Ther. 2004;3:207–18.

    Article  CAS  PubMed  Google Scholar 

  44. Hsu YC, Kao CY, Chung YF, Lee DC, Liu JW, Chiu IM. Activation of Aurora A kinase through the FGF1/FGFR signaling axis sustains the stem cell characteristics of glioblastoma cells. Exp Cell Res. 2016;344:153–66.

    Article  CAS  PubMed  Google Scholar 

  45. Liu Z, Wang F, Zhou ZW, Xia HC, Wang XY, Yang YX, et al. Alisertib induces G(2)/M arrest, apoptosis, and autophagy via PI3K/Akt/mTOR- and p38 MAPK-mediated pathways in human glioblastoma cells. Am J Transl Res. 2017;9:845–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Alafate W, Wang M, Zuo J, Wu W, Sun L, Liu C, et al. Targeting Aurora kinase B attenuates chemoresistance in glioblastoma via a synergistic manner with temozolomide. Pathol Res Pract. 2019;215:152617.

    Article  CAS  PubMed  Google Scholar 

  47. Borges KS, Castro-Gamero AM, Moreno DA, da Silva Silveira V, Brassesco MS, de Paula Queiroz RG, et al. Inhibition of Aurora kinases enhances chemosensitivity to temozolomide and causes radiosensitization in glioblastoma cells. J Cancer Res Clin Oncol. 2012;138:405–14.

    Article  CAS  PubMed  Google Scholar 

  48. Frangini A, Sjöberg M, Roman-Trufero M, Dharmalingam G, Haberle V, Bartke T, et al. The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes. Mol Cell. 2013;51:647–61.

    Article  CAS  PubMed  Google Scholar 

  49. Briassouli P, Chan F, Savage K, Reis-Filho JS, Linardopoulos S. Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha. Cancer Res. 2007;67:1689–95.

    Article  CAS  PubMed  Google Scholar 

  50. Löwenberg B, Muus P, Ossenkoppele G, Rousselot P, Cahn JY, Ifrah N, et al. Phase 1/2 study to assess the safety, efficacy, and pharmacokinetics of barasertib (AZD1152) in patients with advanced acute myeloid leukemia. Blood. 2011;118:6030–6.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Tsuboi K, Yokozawa T, Sakura T, Watanabe T, Fujisawa S, Yamauchi T, et al. A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia. Leuk Res. 2011;35:1384–9.

    Article  CAS  PubMed  Google Scholar 

  52. Schwartz GK, Carvajal RD, Midgley R, Rodig SJ, Stockman PK, Ataman O, et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Investig N. Drugs. 2013;31:370–80.

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge the funding from the Department of Science and Technology (DST), Government of India grant EMR/2017/004994 (SD). Department of Atomic Energy (DAE), Government of India grant 1/3(7)/2020/TMC/R&D-II/8823 (SD). Department of Atomic Energy (DAE), Government of India grant 1/3(6)/2020/TMC/R&D-II/3805 (SD). We acknowledge ACTREC animal facility for timely supply of animals.

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Authors and Affiliations

  1. Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Tejashree Mahaddalkar, Archisman Banerjee, Madhura Ketkar & Shilpee Dutt

  2. Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India

    Tejashree Mahaddalkar, Archisman Banerjee, Madhura Ketkar & Shilpee Dutt

  3. Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India

    Rahul Thorat

  4. Department of Medical Oncology, Tata Memorial Centre, Navi Mumbai, India

    Nilesh Gardi

  5. Shilpee Dutt Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, India

    Shilpee Dutt

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Contributions

Conceptualization: TM, SD; Methodology: TM, AB, MK, RT, and NG; Resources: SD; Funding Acquisition: SD; Project administration: SD; Supervision: SD; Original Draft: TM and SD; Review & Editing: TM and SD.

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Correspondence to Shilpee Dutt.

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Fresh naïve GBM patient tumor samples were obtained during surgery after approval from the Tata Memorial Centre Institutional Ethics Committee (TMC-IEC III) (DCGI Reg. No.: IEC III:- ECR/149/Inst/MH/2013/RR-24) (TMC project number 77) with a written consent form in a language understood by the patients. All animal experiments were licensed through the Laboratory Animal Facility at ACTREC, TMC (project number 33/2023). All animal experiments followed Institutional Animal Ethics committee, ACTREC approved protocols. All methods were performed in accordance with the relevant guidelines and regulations.

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Mahaddalkar, T., Banerjee, A., Ketkar, M. et al. Aurora Kinase A and B inhibition abrogates ‘Neosis’, a non-mitotic cell division of GBM residual cells and prevents GBM recurrence. Oncogene 44, 2103–2115 (2025). https://doi.org/10.1038/s41388-025-03372-6

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