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, N. Mehrdad, D. M. Nguyen, N. G. Ayad, P. Rai, A. J. Capobianco, D. J. Robbins

Research output: Contribution to journalArticle

9 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Rodriguez-Blanco, J., Pednekar, L., Penas, C., Li, B., Martin, V., Long, J., Lee, E., Weiss, W. A., Rodriguez, C., Mehrdad, N., Nguyen, D. M., Ayad, N. G., Rai, P., Capobianco, A. 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