A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Moriarity, Branden S.; Otto, George M.; Rahrmann, Eric P.; Rathe, Susan K.; Wolf, Natalie K.; Weg, Madison T.; Manlove, Luke S.; LaRue, Rebecca S.; Temiz, Nuri A.; Molyneux, Sam D.; Choi, Kwangmin; Holly, Kevin J; Sarver, Aaron L.; Scott, Milcah C.; Forster, Colleen L.; Modiano, Jaime F.; Khanna, Chand; Hewitt, Stephen M.; Khokha, Rama; Yang, Yi; Görlick, Richard; Dyer, Michael A.; Largaespada, David A.

doi:10.1038/ng.3293

Cited by 211 publications

(260 citation statements)

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“…In addition, in many cases, only a single transposon insertion was present at a CCG in tumor cells, suggesting that many CCGs are functioning as haploinsufficient TSGs. This is similar to what has been observed in other SB mutagenesis screens performed in solid tumors (18)(19)(20)(21)(22)(23)(24)(25)(26).…”

Section: Sb Mutagenesis Promotes the Development Of Multiple Breast Csupporting

confidence: 77%

“…Identification of Trunk Driver Genes. Most CCGs identified by SB mutagenesis are thought to function during late stages of tumor progression (18)(19)(20)(21)(22)(23)(24)(25)(26). To identify the CCGs that function early in mammary tumor development, we selected transposon insertion sites represented by the highest number of sequencing reads (SB insertions in the CCG in ≥3 tumors with ≥9 reads per tumor), arguing that these insertions would be present in the largest number of tumor cells.…”

Section: Sb Mutagenesis Promotes the Development Of Multiple Breast Cmentioning

confidence: 99%

“…New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18)(19)(20)(21)(22)(23)(24)(25)(26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes.…”

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confidence: 99%

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Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.Sleeping Beauty | breast cancer | TRPS1 | metastasis | tumor suppressors B reast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and basal-like (1-5). Basal-like or triplenegative breast cancer (TNBC) constitutes 10-20% of all breast cancers and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1, 3-5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6-8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9, 10). Mutations in PTEN drive epithelial-mesenchymal transition (EMT) and promote metastasis in TNBC (11-13). Similarly, in mice, heterozygous deletion of Pten induces mammary tumors with basal-like characteristics (14)(15)(16)(17).Despite all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18-26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes. Transposon insertions in tumors thus serve as molecular tags for the high-throughput cloning and identification of cancer genes. In addition, because transposon insertions are PCR-amplified before they are sequenced, insertional mutations in cancer genes that are present in only a small fraction of tumor cells can be identified. Transposon mutagenesis can thus identify genes that are functioning at th...

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Section: Sb Mutagenesis Promotes the Development Of Multiple Breast Csupporting

confidence: 77%

Section: Sb Mutagenesis Promotes the Development Of Multiple Breast Cmentioning

confidence: 99%

mentioning

confidence: 99%

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Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…It is often associated with massive chromosomal rearrangements, cytogenetic aberrations, and numerous mutations [25]. Numerous cytogenetic and molecu-lar studies of osteosarcoma have been conducted in recent years yielding interesting results but often with conlicting indings [26].…”

Section: Chromosomal Abnormalitiesmentioning

confidence: 99%

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

Smeester¹,

Moriarity²,

Beitz³

2017

Osteosarcoma - Biology, Behavior and Mechanisms

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Osteosarcoma is the most common primary cancer of the bone and third most common cancer in children and adolescents with approximately 900 new cases annually in the United States. A major facet of osteosarcoma is its high level of genomic instability, in particular chromosomal instability, which is the result of increased or decreased chromosome number in a cell. Furthermore, pain is the most common symptomatic feature of osteosarcoma that lacks efective therapy. Pain in osteosarcoma is relatively more complicated than many other painful conditions requiring a more thorough understanding of its etiology, pathobiology, and neurobiology to allow the development of beter therapies for reducing pain in osteosarcoma patients. Studies are underway to deine the diverse modalities of presentation, growth, development, metastases, and nociception in osteosarcoma. New data from human studies in combination with data from studies incorporating transgenic mouse models of osteosarcoma are providing valuable insights into the mechanisms underlying the development of both the tumor and the tumor-induced pain. These new data will undoubtedly lead to improved prognoses, as well as the development of novel therapeutics that will signiicantly decrease bone cancer pain.

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“…It was reported that Sema6D regulates the late-phase activity of T cells during the primary immune response (14), and it functions as a promoter of tissue remodeling (15) and tumorigenesis (16). Additionally, Sema6D also functions as a ligand for plexin-A1 during T cell-dendritic cell interactions (6).…”

Section: Introductionmentioning

confidence: 99%

Expression of semaphorin 6D and its receptor plexin-A1 in gastric cancer and their association with tumor angiogenesis

Chen

et al. 2016

Oncology Letters

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Abstract. The semaphorin and plexin family of ligands and receptor proteins provides important axon growth and guidance cues required for development. In recent years, studies have expanded their role in the regulation of cardiac morphogenesis and tumorigenesis. However, the mechanism responsible for their role in regulating cancer development and progression has not been clarified. In the present study, semaphorin 6D (Sema6D) and its receptor plexin-A1 were identified to be expressed at high levels in vascular epithelial cells within gastric cancer, and were positively correlated with vascular endothelial growth factor receptor 2 (VEGFR2). These findings verify our hypothesis that Sema6D and plexin-A1 may be closely associated with tumor angiogenesis. Combined with experimental observations in the MGC803 gastric cancer cell line, it was observed that knocking down plexin-A1 signaling led to a decreased expression of VEGFR2 at the messenger RNA and protein levels. Sema6D recognized and activated plexin-A1, which subsequently activated its downstream target, VEGFR2. The activation of VEGFR2 functioned as a positive regulator of tumor angiogenesis. Our data provided an understanding of the complex signaling cascades involved in the angiogenesis-related pathway in tumor cells. In light of our observations, pharmacological interventions targeting Sema6D/plexin-A1/VEGFR2 signaling may potentially be used as a target for the development of novel anti-angiogenic drugs in gastric cancer. IntroductionThe semaphor in fam ily is a la rge super-protei n fa m ily cont a in ing secreted, t ra nsmembra ne a nd glycosylphosphatidylinositol-linked proteins, and it has been divided into eight hypotypes based on their structures and amino acid sequence similarity: Invertebrate semaphorins consist of classes 1 and 2, while classes 3-7 are vertebrate semaphorins (with the exception of class 5C semaphorins, which are encoded by viral genomes) (1). The semaphorin family was initially identified to be involved in mediating axonal guidance in the developing nervous system (2). Certain members of the semaphorin family have been also shown to exert diverse and important functions in other physiological processes, including heart morphogenesis (3,4), vascular growth (5), immune cell regulation (6) and tumor progression (7,8). Important regulatory functions of certain members of the semaphorin family within tumor angiogenesis have been reported. For example, semaphorin 3A (Sema3A) inhibits angiogenesis through competition for vascular endothelial growth factor (VEGF) (9), and Sema3B has also been indicated as a putative tumor suppressor that inhibits tumor growth and angiogenesis (10). By contrast, Sema3C presumably may promote angiogenesis by stimulating integrin phosphorylation and VEGF120 secretion (11), and Sema4D has been demonstrated to serve a role in tumor-induced angiogenesis (12).Sema6D, mapped on chromosome 2, is the best characterized factor of the class 6 semaphorins, which are single-pass membrane-bound semaphorins (13). It wa...

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A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis

Cited by 211 publications

References 84 publications

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

Expression of semaphorin 6D and its receptor plexin-A1 in gastric cancer and their association with tumor angiogenesis

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