TY - JOUR
T1 - Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma
AU - Rodriguez-Blanco, J.
AU - Pednekar, L.
AU - Penas, C.
AU - Li, B.
AU - Martin, V.
AU - Long, J.
AU - Lee, E.
AU - Weiss, W. A.
AU - Rodriguez, C.
AU - Mehrdad, N.
AU - Nguyen, D. M.
AU - Ayad, N. G.
AU - Rai, P.
AU - Capobianco, A. J.
AU - Robbins, D. J.
N1 - Funding Information:
We would like to thank members of the Robbins, Capobianco and Pei laboratories for providing their insights during discussions regarding this manuscript. Also, we would like to acknowledge the skilled assistance of the Sylvester Cancer Center Flow Cytometry Core. Funding: Alex Lemonade Stand Foundation M1201547 (DJR), 1R21NS096502-01 (DJR), The University of Miami Women’s Cancer Association (DJR), B*Cured 2016 (DJR), Childhood Brain Tumor Foundation (JR-B), FICYT POST10-27 (JR-B), funds from the Sylvester Cancer Center (DJR), NIH R01GM081635 (EL), and R01GM103926 (EL).
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/11/9
Y1 - 2017/11/9
N2 - 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.
AB - 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.
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U2 - 10.1038/onc.2017.232
DO - 10.1038/onc.2017.232
M3 - Article
C2 - 28714964
AN - SCOPUS:85033440017
VL - 36
SP - 6306
EP - 6314
JO - Oncogene
JF - Oncogene
SN - 0950-9232
IS - 45
ER -