title: Radiation-induced homotypic cell fusions of innately resistant glioblastoma cells mediate their sustained survival and recurrence.
abstract: Understanding of molecular events underlying resistance and relapse in glioblastoma (GBM) is hampered due to lack of accessibility to resistant cells from patients undergone therapy. Therefore, we mimicked clinical scenario in an in vitro cellular model developed from five GBM grade IV primary patient samples and two cell lines. We show that upon exposure to lethal dose of radiation, a subpopulation of GBM cells, innately resistant to radiation, survive and transiently arrest in G2/M phase via inhibitory pCdk1(Y15). Although arrested, these cells show multinucleated and giant cell phenotype (MNGC). Significantly, we demonstrate that these MNGCs are not pre-existing giant cells from parent population but formed via radiation-induced homotypic cell fusions among resistant cells. Furthermore, cell fusions induce senescence, high expression of senescence-associated secretory proteins (SASPs) and activation of pro-survival signals (pAKT, BIRC3 and Bcl-xL) in MNGCs. Importantly, following transient non-proliferation, MNGCs escape senescence and despite having multiple spindle poles during mitosis, they overcome mitotic catastrophe to undergo normal cytokinesis forming mononucleated relapse population. This is the first report showing radiation-induced homotypic cell fusions as novel non-genetic mechanism in radiation-resistant cells to sustain survival. These data also underscore the importance of non-proliferative phase in resistant glioma cells. Accordingly, we show that pushing resistant cells into premature mitosis by Wee1 kinase inhibitor prevents pCdk1(Y15)-mediated cell cycle arrest and relapse. Taken together, our data provide novel molecular insights into a multistep process of radiation survival and relapse in GBM that can be exploited for therapeutic interventions.
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Ekjot
authors: E
authors: Kaur
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Jacinth
authors: J
authors: Rajendra
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Shailesh
authors: S
authors: Jadhav
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Epari
authors: E
authors: Shridhar
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Jayant Sastri
authors: JS
authors: Goda
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
authors: Aliasgar
authors: A
authors: Moiyadi
authors: Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India sdutt@actrec.gov.in.
authors: Shilpee
authors: S
authors: Dutt
mesh_terms: D017209:Apoptosis / Q000235:genetics; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D001932:Brain Neoplasms / Q000235:genetics*; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D002459:Cell Fusion; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D018844:Cyclin-Dependent Kinases; D015726:Giant Cells / Q000528:radiation effects; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000528:radiation effects; D008938:Mitosis / Q000235:genetics / Q000528:radiation effects; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D051020:bcl-X Protein; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases