TGF-β and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma

Aiguo Li; John C Hancock; Martha Quezado; Susie Ahn; Nicole Briceno; Orieta Celiku; Surabhi Ranjan; Orwa Aboud; Nicole Colwell; Sun A Kim; Edjah Nduom; Skyler Kuhn; Deric M Park; Elizabeth Vera; Ken Aldape; Terri S Armstrong; Mark R Gilbert

doi:10.1093/noajnl/vdad164

TGF-β and BMP signaling are associated with the transformation of glioblastoma to gliosarcoma and then osteosarcoma

Neurooncol Adv. 2023 Dec 19;6(1):vdad164. doi: 10.1093/noajnl/vdad164. eCollection 2024 Jan-Dec.

Authors

Aiguo Li¹, John C Hancock¹, Martha Quezado², Susie Ahn¹, Nicole Briceno¹, Orieta Celiku¹, Surabhi Ranjan¹, Orwa Aboud³, Nicole Colwell¹, Sun A Kim², Edjah Nduom⁴, Skyler Kuhn⁵, Deric M Park¹, Elizabeth Vera¹, Ken Aldape², Terri S Armstrong¹, Mark R Gilbert¹

Affiliations

¹ Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA.
² Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland, USA.
³ Department of Neurology and Neurological Surgery, University of California, Davis, Sacramento, California, USA.
⁴ Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
⁵ Research Technology Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.

Abstract

Background: Gliosarcoma, an isocitrate dehydrogenase wildtype (IDH-WT) variant of glioblastoma, is defined by clonal biphasic differentiation into gliomatous and sarcomatous components. While the transformation from a glioblastoma to gliosarcoma is uncommon, the subsequent transformation to osteosarcoma is rare but may provide additional insights into the biology of these typically distinct cancers. We observed a patient initially diagnosed with glioblastoma, that differentiated into gliosarcoma at recurrence, and further evolved to osteosarcoma at the second relapse. Our objective was to characterize the molecular mechanisms of tumor progression associated with this phenotypic transformation.

Methods: Tumor samples were collected at all 3 stages of disease and RNA sequencing was performed to capture their transcriptomic profiles. Sequential clonal evolution was confirmed by the maintenance of an identical PTEN mutation throughout the tumor differentiation using the TSO500 gene panel. Publicly available datasets and the Nanostring nCounter technology were used to validate the results.

Results: The glioblastoma tumor from this patient possessed mixed features of all 3 TCGA-defined transcriptomic subtypes of an IDH-WT glioblastoma and a proportion of osteosarcoma signatures were upregulated in the original tumor. Analysis showed that enhanced transforming growth factor-β (TGF-β) and bone morphogenic protein signaling was associated with tumor transformation. Regulatory network analysis revealed that TGF-β family signaling committed the lineage tumor to osteogenesis by stimulating the expression of runt-related transcription factor 2 (RUNX2), a master regulator of bone formation.

Conclusions: This unusual clinical case provided an opportunity to explore the modulators of longitudinal sarcomatous transformation, potentially uncovering markers indicating predisposition to this change and identification of novel therapeutic targets.

Keywords: TGF-β signaling; glioblastoma; gliosarcoma; osteosarcoma.

Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.