Citations 2
Myosin IIA suppresses glioblastoma development in a mechanically sensitive manner
Picariello, Hannah S., Kenchappa, Rajappa S., Crish, James F. , Dovas, Athanassios, Pogoda, Katarzyna , McMahon, Mariah, Bell, Emily , Chandrasekharan, Unnikrishnan M. , Luu, Amanda, West, Rita, Canoll, Peter , Odde, David J. , Janmey, Paul A. , Egelhoff, Thomas, Rosenfeld, Steven S. , McMahon, Mariah , Odde, David J , Rai, Vandana, Luu, Amanda, Lammerding, Jan
Proceedings of the National Academy of Sciences | June 25, 2019 | Volume: 116 | Issue: 31 | Pages: 15550-15559
Significance Glioblastoma, the most common and lethal of primary brain tumors, can diffusely infiltrate brain. Because the components of the cytoskeleton that drive tumor invasion are nonredundant, they have been attractive targets for blocking glioblastoma dispersion. However, we find that while targeting one of these—the molecular motor myosin IIA—effectively blocks glioblastoma invasion, it enhances tumor proliferation and lethality. In this study, we have found that myosin IIA functions as a tumor suppressor by reducing signaling of two oncogenes—ERK1/2 and NF-κB—in a manner regulated by the mechanics of the tumor and surrounding brain. Our results also argue that effective treatment of glioblastoma will require inhibiting targets that drive both invasion and proliferation.
Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors
Beckmann, Pauline J. , Larsson, Alex T. , Ostergaard, Jason, Wagner, Sandra, Rahrmann, Eric P. , Shamsan, Ghaidan A. , Otto, George M. , Williams, Rory L. , Wang, Jun , Lee, Catherine , Tschida, Barbara R. , Das, Paramita , Dubuc, Adrian M. , Moriarity, Branden S. , Picard, Daniel , Wu, Xiaochong , Rosemarie, Quincy , Krebs, Ryan D., Molan, Amy M. , Demer, Addison M. , Frees, Michelle M. , Rizzardi, Anthony E., Schmechel, Stephen C. , Jenkins, Robert B. , Wechsler‐Reya, Robert J. , Odde, David J. , Taylor, Michael D. , Sarver, Aaron L. , Largaespada, David A. , Rahrmann, Eric P , Shamsan, Ghaidan A , Williams, Rory L , Picard, Daniel , Rosemarie, Quincy , Odde, David J , Larson, Jon D. , Wagner, Sandra, Tschida, Barbara R , Rodríguez, Fausto J. , Krebs, Ryan D., Eberhart, Charles G. , Huang, Annie , Largaespada, David A.
Cancer Research | January 23, 2019 | Volume: 79 | Issue: 5 | Pages: 905-917
Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.