<i>Sleeping Beauty</i> Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Beckmann, Pauline J.; Larson, Jon D.; 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; Rodríguez, Fausto J.; Rosemarie, Quincy; Krebs, Ryan; Molan, Amy M.; Demer, Addison M.; Frees, Michelle M.; Rizzardi, Anthony E.; Schmechel, Stephen C.; Eberhart, Charles G.; Jenkins, Robert B.; Wechsler‐Reya, Robert J.; Odde, David J.; Huang, Annie; Taylor, Michael D.; Sarver, Aaron L.; Largaespada, David A.

doi:10.1158/0008-5472.can-18-1261

Cited by 40 publications

(37 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tol2 (isolated from medaka fish) and insect-derived PB and Minos have also been used in mutagenesis in vertebrates such as the mouse and zebrafish [16][17][18]. Sleeping Beauty (SB) is derived from elements cloned from salmonid fish and has been widely used in insertional mutagenesis screens in mice [19][20][21][22][23][24][25][26][27][28][29] and shown to be active in other vertebrates including cultured cell lines, rats, zebrafish, and Xenopus [19,[30][31][32].…”

Section: Transposon Basicsmentioning

confidence: 99%

“…Subsequently, a conditional SB mouse was created (R26-lsl-SB11), allowing tissue and temporal-specific transposition and modeling of very specific cancers [23]. For example, we used Nestin-driven Cre recombinase to drive SB expression solely in the developing central nervous system and to identify novel genetic drivers of childhood brain tumors [28]. The expression profiles of many of the Cre strains described in Table 1 have been characterized by The Jackson Laboratory [47].…”

Section: Transposons To Model Human Cancer In Micementioning

confidence: 99%

“…Another example is Foxr2. Transposon mutagenesis studies identified Foxr2 as a strong candidate driver of malignant peripheral nerve sheath tumors (MPNST), osteosarcoma, and medulloblastoma [28,29,48,96]. Interestingly, human FOXR2 is amplified and overexpressed in a subset of human MPNST and activated by translocation or amplification in a subset of human embryonal tumors of the central nervous system [29,110].…”

Section: Identification Of Rare Eventsmentioning

confidence: 99%

See 2 more Smart Citations

Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities

Beckmann

Largaespada

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Transposon mutagenesis has been used to model many types of human cancer in mice, leading to the discovery of novel cancer genes and insights into the mechanism of tumorigenesis. For this review, we identified over twenty types of human cancer that have been modeled in the mouse using Sleeping Beauty and piggyBac transposon insertion mutagenesis. We examine several specific biological insights that have been gained and describe opportunities for continued research. Specifically, we review studies with a focus on understanding metastasis, therapy resistance, and tumor cell of origin. Additionally, we propose further uses of transposon-based models to identify rarely mutated driver genes across many cancers, understand additional mechanisms of drug resistance and metastasis, and define personalized therapies for cancer patients with obesity as a comorbidity.

show abstract

Section: Transposon Basicsmentioning

confidence: 99%

Section: Transposons To Model Human Cancer In Micementioning

confidence: 99%

Section: Identification Of Rare Eventsmentioning

confidence: 99%

See 1 more Smart Citation

Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities

Beckmann

Largaespada

2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another approach involves insertional mutagenesis with the transposase Sleeping Beauty that when conditionally expressed in Nestin‐Cre mice together with a Trp53 mutation (Nestin‐Cre/T2‐ONC × Trp53LslR270H × Rosa26LslSB11/+) or PTEN knock‐out (Nestin‐Cre/T2‐ONC × PTEN Flox/Flox × Rosa26LslSB11/+) induces SHH or Group 3/Group 4 medulloblastoma .…”

Section: Approaches To Modeling Medulloblastoma In Micementioning

confidence: 99%

Modeling pediatric medulloblastoma

Roussel

Stripay

2019

Brain Pathology

View full text Add to dashboard Cite

Mouse models of medulloblastoma have proven to be instrumental in understanding disease mechanisms, particularly the role of epigenetic and molecular drivers, and establishing appropriate preclinical pipelines. To date, our research community has developed murine models for all four groups of medulloblastoma, each of which will be critical for the identification and development of new therapeutic approaches. Approaches to modeling medulloblastoma range from genetic engineering with CRISPR/Cas9 or in utero electroporation, to orthotopic and patient-derived orthotopic xenograft systems. Each approach or model presents unique advantages that have ultimately contributed to an appreciation of medulloblastoma heterogeneity and the clinical obstacles that exist for this patient population.

show abstract

“…In fact, SB-based mouse models of cancer have provided an ideal system in which to test the molecular mechanisms of tumor initiation and sensitivity to pathway-targeted therapy. [19][20][21] We have developed a preclinical, spontaneous, HPV16 buccal tumor model using submucosal injection of oncogenic plasmids expressing HPV16 E6/E7, NRas G12V , luciferase and SB transposase, followed by electroporation (EP) in the buccal mucosa. 22 In this study, we describe a clinical relevance, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive tumor microenvironment (TME) of metastatic peritoneal cancers with features consistent with HGSC.…”

Section: Introductionmentioning

confidence: 99%

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

Tseng

Park

Lam

et al. 2020

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundPeritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity.MethodsWe developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice).ResultsSimilar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+and CD8+T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth.ConclusionsOverall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.

show abstract

Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors

Cited by 40 publications

References 49 publications

Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities

Transposon Insertion Mutagenesis in Mice for Modeling Human Cancers: Critical Insights Gained and New Opportunities

Modeling pediatric medulloblastoma

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

Contact Info

Product

Resources

About