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

AUTHORS

Rodriguez-Blanco JJ , Pednekar L L , Penas C C , Li B B , Martin V V , Long J J , Lee E E , Weiss WA W A , Rodriguez C C , Mehrdad N N , Nguyen DM D M , Ayad NG N G , Rai P P , Capobianco AJ A J , Robbins DJ D J . Oncogene. 2017 7 17; ().

PMID: 28714964[PubMed].
PMCID: PMC5680121.

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.Oncogene advance online publication, 17 July 2017; doi:10.1038/onc.2017.232.