Epigenetic regulation in SHH-subgroup medulloblastoma formation
Hematology, Oncology
Final Report Abstract
Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors and arises in the cerebellum. Based on worldwide molecular characterization studies, MBs are now classified into at least four subgroups: WNT, sonic hedgehog (SHH), Group3 and Group4. Among these subgroups, the etiology of SHH-subgroup MBs (MBSHH) that comprise approximately 30% of human MBs has been most clearly established, especially due to their faithful animal models. MBSHHs are derived from cerebellar granule neuron precursors (GNPs) according to abnormal activation of the SHH signaling pathway. The blockade of the SHH signaling with Smoothened (Smo) inhibitors cyclopamine and GDC-0449 led to tumor regression, suggesting involvement of SHH signaling in tumor progression and maintenance. Nevertheless, while Smo inhibitors are attractive candidate drugs, potent side effects and resistance induction have been reported. In addition, gain of function mutations and amplification/overexpression of effector genes downstream of Smo result in primary resistance of tumors against these drugs. Therefore, other approaches to repress SHH signaling and/or its downstream targets as well as additional oncogenic signaling remain to be desperately needed. In addition to SHH signaling, previous study has also proved requirement of additional second genetic hits to accelerate tumorigenesis in transition from hyperplasia into malignant tumors, which could confer mutation-dependent oncogenic characteristics on the tumor cells. Therefore, understanding of the secondary genetic hits would be also a promising approach for establishment of novel therapeutic avenues. In this study, we identified frequent mutations in BCOR in human MBSHHs. Using an appropriate animal model of MBSHH, we found that Bcor mutations accelerate tumor progression by overactivating Igf2, which acts downstream of SHH signaling. Furthermore, understanding the Igf2 expression by BCOR in terms of genomic structure has revealed some of the knowledge about how Igf2 expression is regulated in cancer. Our recent analysis across various cancer types is also revealing a positive relationship between BCOR deficiency and Igf2 expression, and we believe that our findings have uncovered an important mechanism common to a variety of cancers that is not limited to the framework of pediatric brain tumors.
Publications
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Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme. Nature Communications, 8(1).
Feng, Weijun; Kawauchi, Daisuke; Körkel-Qu, Huiqin; Deng, Huan; Serger, Elisabeth; Sieber, Laura; Lieberman, Jenna Ariel; Jimeno-González, Silvia; Lambo, Sander; Hanna, Bola S.; Harim, Yassin; Jansen, Malin; Neuerburg, Anna; Friesen, Olga; Zuckermann, Marc; Rajendran, Vijayanad; Gronych, Jan; Ayrault, Olivier; Korshunov, Andrey; ... & Liu, Hai-Kun
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Novel MYC-driven medulloblastoma models from multiple embryonic cerebellar cells. Oncogene, 36(37), 5231-5242.
Kawauchi, D.; Ogg, R. J.; Liu, L.; Shih, D. J. H.; Finkelstein, D.; Murphy, B. L.; Rehg, J. E.; Korshunov, A.; Calabrese, C.; Zindy, F.; Phoenix, T.; Kawaguchi, Y.; Gronych, J.; Gilbertson, R. J.; Lichter, P.; Gajjar, A.; Kool, M.; Northcott, P. A.; Pfister, S. M. & Roussel, M. F.
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Aberrant ERBB4-SRC Signaling as a Hallmark of Group 4 Medulloblastoma Revealed by Integrative Phosphoproteomic Profiling. Cancer Cell, 34(3), 379-395.e7.
Forget, Antoine; Martignetti, Loredana; Puget, Stéphanie; Calzone, Laurence; Brabetz, Sebastian; Picard, Daniel; Montagud, Arnau; Liva, Stéphane; Sta, Alexandre; Dingli, Florent; Arras, Guillaume; Rivera, Jaime; Loew, Damarys; Besnard, Aurore; Lacombe, Joëlle; Pagès, Mélanie; Varlet, Pascale; Dufour, Christelle; Yu, Hua; ... & Ayrault, Olivier
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CRISPR-mediated Loss of Function Analysis in Cerebellar Granule Cells Using <em>In Utero</em> Electroporation-based Gene Transfer. Journal of Visualized Experiments, 136.
Feng, Weijun; Herbst, Lena; Lichter, Peter; Pfister, Stefan M.; Liu, Hai-Kun & Kawauchi, Daisuke
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YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis. Nature Communications, 10(1).
Pajtler, Kristian W.; Wei, Yiju; Okonechnikov, Konstantin; Silva, Patricia B. G.; Vouri, Mikaella; Zhang, Lei; Brabetz, Sebastian; Sieber, Laura; Gulley, Melissa; Mauermann, Monika; Wedig, Tatjana; Mack, Norman; Imamura, Kawasawa Yuka; Sharma, Tanvi; Zuckermann, Marc; Andreiuolo, Felipe; Holland, Eric; Maass, Kendra; Körkel-Qu, Huiqin; ... & Kawauchi, Daisuke
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Functional loss of a noncanonical BCOR–PRC1.1 complex accelerates SHH-driven medulloblastoma formation. Genes & Development, 34(17-18), 1161-1176.
Kutscher, Lena M.; Okonechnikov, Konstantin; Batora, Nadja V.; Clark, Jessica; Silva, Patricia B.G.; Vouri, Mikaella; van Rijn, Sjoerd; Sieber, Laura; Statz, Britta; Gearhart, Micah D.; Shiraishi, Ryo; Mack, Norman; Orr, Brent A.; Korshunov, Andrey; Gudenas, Brian L.; Smith, Kyle S.; Mercier, Audrey L.; Ayrault, Olivier; Hoshino, Mikio; ... & Kawauchi, Daisuke
