Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma

Michelle Monje, Siddhartha S. Mitra, Morgan E. Freret, Tal B. Raveh, James Kim, Marilyn Masek, Joanne L. Attema, Gordon Li, Terri Haddix, Michael S B Edwards, Paul G. Fisher, Irving L. Weissman, David H. Rowitch, Hannes Vogel, Albert J. Wong, Philip A. Beachy

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG selfrenewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.

Original languageEnglish (US)
Pages (from-to)4453-4458
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number11
DOIs
StatePublished - Mar 15 2011

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Hedgehogs
Glioma
Brain Stem Neoplasms
Pons
Neoplasms
Heterografts
Hypertrophy
Brain Stem
Animal Models
Pediatrics
Incidence
Population

Keywords

  • Brainstem glioma
  • Cancer stem cells
  • Hedgehog pathway

ASJC Scopus subject areas

  • General

Cite this

Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. / Monje, Michelle; Mitra, Siddhartha S.; Freret, Morgan E.; Raveh, Tal B.; Kim, James; Masek, Marilyn; Attema, Joanne L.; Li, Gordon; Haddix, Terri; Edwards, Michael S B; Fisher, Paul G.; Weissman, Irving L.; Rowitch, David H.; Vogel, Hannes; Wong, Albert J.; Beachy, Philip A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 11, 15.03.2011, p. 4453-4458.

Research output: Contribution to journalArticle

Monje, M, Mitra, SS, Freret, ME, Raveh, TB, Kim, J, Masek, M, Attema, JL, Li, G, Haddix, T, Edwards, MSB, Fisher, PG, Weissman, IL, Rowitch, DH, Vogel, H, Wong, AJ & Beachy, PA 2011, 'Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma', Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 11, pp. 4453-4458. https://doi.org/10.1073/pnas.1101657108
Monje, Michelle ; Mitra, Siddhartha S. ; Freret, Morgan E. ; Raveh, Tal B. ; Kim, James ; Masek, Marilyn ; Attema, Joanne L. ; Li, Gordon ; Haddix, Terri ; Edwards, Michael S B ; Fisher, Paul G. ; Weissman, Irving L. ; Rowitch, David H. ; Vogel, Hannes ; Wong, Albert J. ; Beachy, Philip A. / Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 11. pp. 4453-4458.
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