Haploinsufficiency of phosphodiesterase 10A activates PI3K/AKT signaling independent of PTEN to induce an aggressive glioma phenotype
- Nicholas Nuechterlein1,
- Allison Shelbourn1,
- Frank Szulzewsky2,
- Sonali Arora2,
- Michelle Casad3,
- Siobhan Pattwell4,
- Leyre Merino-Galan4,
- Erik Sulman5,
- Sumaita Arowa1,
- Neriah Alvinez1,
- Miyeon Jung6,
- Desmond Brown6,
- Kayen Tang7,
- Sadhana Jackson7,
- Stefan Stoica8,
- Prashant Chittaboina8,
- Yeshavanth K. Banasavadi-Siddegowda9,
- Hans-Georg Wirsching10,
- Nephi Stella11,
- Linda Shapiro12,
- Patrick Paddison2,
- Anoop P. Patel13,
- Mark R. Gilbert14,
- Zied Abdullaev15,
- Kenneth Aldape15,
- Drew Pratt15,
- Eric C. Holland2 and
- Patrick J. Cimino1
- 1Neuropathology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 2Human Biology Division, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA;
- 3Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington 98195, USA;
- 4Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington 98145, USA;
- 5Department of Radiation Oncology, New York University Grossman School of Medicine, New York, New York 11220, USA;
- 6Neurosurgical Oncology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 7Developmental Therapeutics and Pharmacology Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 8Neurosurgery Unit for Pituitary and Inheritable Diseases, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 9Molecular and Therapeutics Unit, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 10Department of Neurology, University Hospital, University of Zurich, Zurich 8091, Switzerland;
- 11Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA;
- 12Paul G. Allen School of Computer Science and Engineering, University of Washington, Seattle, Washington 98195, USA;
- 13Department of Neurosurgery, Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina 27710, USA;
- 14Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA;
- 15Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20814, USA
- Corresponding author: pj.cimino{at}nih.gov
Abstract
Glioblastoma is universally fatal and characterized by frequent chromosomal copy number alterations harboring oncogenes and tumor suppressors. In this study, we analyzed exome-wide human glioblastoma copy number data and found that cytoband 6q27 is an independent poor prognostic marker in multiple data sets. We then combined CRISPR–Cas9 data, human spatial transcriptomic data, and human and mouse RNA sequencing data to nominate PDE10A as a potential haploinsufficient tumor suppressor in the 6q27 region. Mouse glioblastoma modeling using the RCAS/tv-a system confirmed that Pde10a suppression induced an aggressive glioma phenotype in vivo and resistance to temozolomide and radiation therapy in vitro. Cell culture analysis showed that decreased Pde10a expression led to increased PI3K/AKT signaling in a Pten-independent manner, a response blocked by selective PI3K inhibitors. Single-nucleus RNA sequencing from our mouse gliomas in vivo, in combination with cell culture validation, further showed that Pde10a suppression was associated with a proneural-to-mesenchymal transition that exhibited increased cell adhesion and decreased cell migration. Our results indicate that glioblastoma patients harboring PDE10A loss have worse outcomes and potentially increased sensitivity to PI3K inhibition.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.351350.123.
- Received November 10, 2023.
- Accepted March 27, 2024.
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