Platelet-derived growth factor receptors differentially inform intertumoral and intratumoral heterogeneity
- Youngmi Kim1,
- Eunhee Kim1,
- Qiulian Wu1,
- Olga Guryanova1,
- Masahiro Hitomi1,
- Justin D. Lathia1,2,
- David Serwanski3,
- Andrew E. Sloan4,5,6,
- Robert J. Weil7,
- Jeongwu Lee1,
- Akiko Nishiyama3,
- Shideng Bao1,
- Anita B. Hjelmeland1,8 and
- Jeremy N. Rich1,8
- 1Department of Stem Cell Biology and Regenerative Medicine,
- 2Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA;
- 3Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269, USA,
- 4Department of Neurological Surgery,
- 5Department of Pathology,
- 6Center for Translational Neuroscience, Case Western Reserve University School of Medicine, University Hospitals, Cleveland, Ohio 44106, USA;
- 7Department of Neurosurgery, the Neurological Institute, Burkhardt Brain Tumor and Neuro-oncology Center, Cleveland Clinic, Cleveland, Ohio 44195, USA
Abstract
Growth factor-mediated proliferation and self-renewal maintain tissue-specific stem cells and are frequently dysregulated in cancers. Platelet-derived growth factor (PDGF) ligands and receptors (PDGFRs) are commonly overexpressed in gliomas and initiate tumors, as proven in genetically engineered models. While PDGFRα alterations inform intertumoral heterogeneity toward a proneural glioblastoma (GBM) subtype, we interrogated the role of PDGFRs in intratumoral GBM heterogeneity. We found that PDGFRα is expressed only in a subset of GBMs, while PDGFRβ is more commonly expressed in tumors but is preferentially expressed by self-renewing tumorigenic GBM stem cells (GSCs). Genetic or pharmacological targeting of PDGFRβ (but not PDGFRα) attenuated GSC self-renewal, survival, tumor growth, and invasion. PDGFRβ inhibition decreased activation of the cancer stem cell signaling node STAT3, while constitutively active STAT3 rescued the loss of GSC self-renewal caused by PDGFRβ targeting. In silico survival analysis demonstrated that PDGFRB informed poor prognosis, while PDGFRA was a positive prognostic factor. Our results may explain mixed clinical responses of anti-PDGFR-based approaches and suggest the need for integration of models of cancer as an organ system into development of cancer therapies.
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Footnotes
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↵8 Corresponding authors.
E-mail richj{at}ccf.org.
E-mail hjelmea{at}ccf.org.
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.193565.112.
- Received November 11, 2011.
- Accepted April 16, 2012.
- Copyright © 2012 by Cold Spring Harbor Laboratory Press