Citations 2
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.
Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors
Tschida, Barbara R. , Temiz, Nuri A. , Kuka, Timothy P. , Lee, Lindsey A. , Riordan, Jesse D. , Tierrablanca, Carlos A., Hullsiek, Robert, Wagner, Sandra , Hudson, Wendy A. , Amin, Khalid , Beckmann, Pauline J. , Heuer, Rachel A. , Sarver, Aaron L. , Yang, Ju Dong , Roberts, Lewis R. , Nadeau, Joseph H. , Dupuy, Adam J. , Keng, Vincent W. , Largaespada, David A. , Roberts, Lewis R , Tschida, Barbara R , Linden, Michael A. , Yang, Ju Dong , Largaespada, David A. , Temiz, Nuri A
Cancer Research | October 9, 2017 | Volume: 77 | Issue: 23 | Pages: 6576-6588
Abstract Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using Sleeping Beauty (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the N-acetyltransferase NAT10, which we found to be overexpressed in human steatosis–associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. Cancer Res; 77(23); 6576–88. ©2017 AACR.