1. Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma
- Author
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Priyamvada Rai, Carmen Rodríguez, William A. Weiss, N Mehrdad, Jezabel Rodriguez-Blanco, Dao M. Nguyen, Lina Pednekar, Nagi G. Ayad, Anthony J. Capobianco, David J. Robbins, Jun Long, Ethan Lee, Vanesa Martín, Clara Penas, and Bin Li
- Subjects
Male ,0301 basic medicine ,Cancer Research ,animal structures ,Pyridines ,Vismodegib ,Mice, Transgenic ,Transfection ,Article ,Small Molecule Libraries ,Mice ,Random Allocation ,03 medical and health sciences ,Growth factor receptor ,SOX2 ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Anilides ,Hedgehog Proteins ,Sonic hedgehog ,Cerebellar Neoplasms ,Wnt Signaling Pathway ,Molecular Biology ,TRPC Cation Channels ,Medulloblastoma ,biology ,SOXB1 Transcription Factors ,Veratrum Alkaloids ,Wnt signaling pathway ,Cell cycle ,medicine.disease ,Wnt Proteins ,Disease Models, Animal ,HEK293 Cells ,030104 developmental biology ,Immunology ,embryonic structures ,biology.protein ,Cancer research ,Tumor Suppressor Protein p53 ,Smoothened ,medicine.drug - 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
- Published
- 2017