Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma

J. Rodriguez-Blanco, L. Pednekar, C. Penas, B. Li, V. Martin, J. Long, E. Lee, W. A. Weiss, C. Rodriguez, Mehrdad Nadji, Dao Nguyen, Nagi Ayad, Priyamvada Rai, Anthony J Capobianco, David J Robbins

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

Original languageEnglish (US)
Pages (from-to)6306-6314
Number of pages9
JournalOncogene
Volume36
Issue number45
DOIs
StatePublished - Nov 9 2017

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HhAntag691
Medulloblastoma
Neoplasms
Basal Cell Carcinoma
Recurrence
Growth
Clinical Trials
Survival
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Rodriguez-Blanco, J., Pednekar, L., Penas, C., Li, B., Martin, V., Long, J., ... Robbins, D. J. (2017). Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. Oncogene, 36(45), 6306-6314. https://doi.org/10.1038/onc.2017.232

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. / Rodriguez-Blanco, J.; Pednekar, L.; Penas, C.; Li, B.; Martin, V.; Long, J.; Lee, E.; Weiss, W. A.; Rodriguez, C.; Nadji, Mehrdad; Nguyen, Dao; Ayad, Nagi; Rai, Priyamvada; Capobianco, Anthony J; Robbins, David J.

In: Oncogene, Vol. 36, No. 45, 09.11.2017, p. 6306-6314.

Research output: Contribution to journalArticle

Rodriguez-Blanco, J, Pednekar, L, Penas, C, Li, B, Martin, V, Long, J, Lee, E, Weiss, WA, Rodriguez, C, Nadji, M, Nguyen, D, Ayad, N, Rai, P, Capobianco, AJ & Robbins, DJ 2017, 'Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma', Oncogene, vol. 36, no. 45, pp. 6306-6314. https://doi.org/10.1038/onc.2017.232
Rodriguez-Blanco J, Pednekar L, Penas C, Li B, Martin V, Long J et al. Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. Oncogene. 2017 Nov 9;36(45):6306-6314. https://doi.org/10.1038/onc.2017.232
Rodriguez-Blanco, J. ; Pednekar, L. ; Penas, C. ; Li, B. ; Martin, V. ; Long, J. ; Lee, E. ; Weiss, W. A. ; Rodriguez, C. ; Nadji, Mehrdad ; Nguyen, Dao ; Ayad, Nagi ; Rai, Priyamvada ; Capobianco, Anthony J ; Robbins, David J. / Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma. In: Oncogene. 2017 ; Vol. 36, No. 45. pp. 6306-6314.
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