BMP signaling mediates glioma stem cell quiescence and confers treatment resistance in glioblastoma

• Published in: Scientific reports Vol. 9; no. 1; pp. 14569 - 14
• Main Authors: Sachdeva, Rohit, Wu, Megan, Johnson, Kevin, Kim, Hyunsoo, Celebre, Angela, Shahzad, Uswa, Graham, Maya Srikanth, Kessler, John A., Chuang, Jeffrey H., Karamchandani, Jason, Bredel, Markus, Verhaak, Roel, Das, Sunit
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.10.2019; Nature Publishing Group
• Subjects: 13; 13/100; 13/105; 13/106; 13/51; 13/89; 14; 14/19; 38; 631/67/1922; 631/67/71; 64; Animals; Antineoplastic Agents - pharmacology; Bone Morphogenetic Protein 4 - metabolism; Bone morphogenetic proteins; Bone Morphogenetic Proteins - metabolism; Brain cancer; Brain Neoplasms - therapy; Cell Division; Cell Line, Tumor; Cell Proliferation; Cell self-renewal; Cell signaling; Chemotherapy; Cytotoxicity; Disease Progression; Drug Resistance, Neoplasm; Glioblastoma; Glioblastoma - therapy; Glioma; Glioma cells; Homeostasis; Humanities and Social Sciences; Humans; Mice; Mice, Inbred NOD; multidisciplinary; Neoplasm Recurrence, Local - pathology; Neoplasm Transplantation; Neoplastic Stem Cells - cytology; Phenotype; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Sequence Analysis, RNA; Signal Transduction; Stem cells; Temozolomide; Temozolomide - pharmacology; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51270-1

Despite advances in therapy, glioblastoma remains an incurable disease with a dismal prognosis. Recent studies have implicated cancer stem cells within glioblastoma (glioma stem cells, GSCs) as mediators of therapeutic resistance and tumor progression. In this study, we investigated the role of the transforming growth factor-β (TGF-β) superfamily, which has been found to play an integral role in the maintenance of stem cell homeostasis within multiple stem cell systems, as a mediator of stem-like cells in glioblastoma. We find that BMP and TGF-β signaling define divergent molecular and functional identities in glioblastoma, and mark relatively quiescent and proliferative GSCs, respectively. Treatment of GSCs with BMP inhibits cell proliferation, but does not abrogate their stem-ness, as measured by self-renewal and tumorigencity. Further, BMP pathway activation confers relative resistance to radiation and temozolomide chemotherapy. Our findings define a quiescent cancer stem cell population in glioblastoma that may be a cellular reservoir for tumor recurrence following cytotoxic therapy.