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  • American Association for Cancer Research (AACR)  (4)
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  • American Association for Cancer Research (AACR)  (4)
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  • 1
    Online Resource
    Online Resource
    TALEN-Mediated Somatic Mutagenesis in Murine Models of Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 18 ( 2014-09-15), p. 5311-5321
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 18 ( 2014-09-15), p. 5311-5321
    Abstract: Cancer genome sequencing has identified numerous somatic mutations whose biologic relevance is uncertain. In this study, we used genome-editing tools to create and analyze targeted somatic mutations in murine models of liver cancer. Transcription activator-like effector nucleases (TALEN) were designed against β-catenin (Ctnnb1) and adenomatous polyposis coli (Apc), two commonly mutated genes in hepatocellular carcinoma (HCC), to generate isogenic HCC cell lines. Both mutant cell lines exhibited evidence of Wnt pathway dysregulation. We asked whether these TALENs could create targeted somatic mutations after hydrodynamic transfection into mouse liver. TALENs targeting β-catenin promoted endogenous HCC carrying the intended gain-of-function mutations. However, TALENs targeting Apc were not as efficient in inducing in vivo homozygous loss-of-function mutations. We hypothesized that hepatocyte polyploidy might be protective against TALEN-induced loss of heterozygosity, and indeed Apc gene editing was less efficient in tetraploid than in diploid hepatocytes. To increase efficiency, we administered adenoviral Apc TALENs and found that we could achieve a higher mutagenesis rate in vivo. Our results demonstrate that genome-editing tools can enable the in vivo study of cancer genes and faithfully recapitulate the mosaic nature of mutagenesis in mouse cancer models. Cancer Res; 74(18); 5311–21. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0529
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract B10: The polyploid state plays a tumor-suppressive role in the liver
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 10_Supplement ( 2018-05-15), p. B10-B10
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 10_Supplement ( 2018-05-15), p. B10-B10
    Abstract: Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization normally occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate the function of polyploidy while avoiding irreversible manipulations of essential cell cycle genes, we developed multiple orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as in vivo knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no impact of ploidy alterations on liver function, metabolism, or regeneration, hyperpolyploid mice suppressed and hyperdiploid mice accelerated tumorigenesis in mutagen and high fat induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that ploidy differentially protected the liver from distinct genomic aberrations. Our work suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury. Citation Format: Shuyuan Zhang, Kejin Zhou, Xin Luo, Lin Li, Liem Nguyen, Yu Zhang, Branden Tarlow, Daniel Siegwart, Hao Zhu. The polyploid state plays a tumor-suppressive role in the liver [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B10.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.MOUSEMODELS17-B10
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    Targeting Androgen Receptor (AR)→IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 4 ( 2016-04-01), p. 731-742
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 4 ( 2016-04-01), p. 731-742
    Abstract: Gender disparity has long been considered as a key to fully understand hepatocellular carcinoma (HCC) development. At the same time, immunotherapy related to IL12 still need more investigation before being applied in clinical settings. The aim of this study is to investigate the influence of the androgen receptor (AR) on natural killer (NK) cell–related innate immune surveillance in liver cancer, and provide a novel therapeutic approach to suppress HCC via altering IL12A. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mouse model, we identified the role of AR in modulating NK cell cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. IHC was performed for sample staining. Our results showed AR could suppress IL12A expression at the transcriptional level via direct binding to the IL12A promoter region that resulted in repressing efficacy of NK cell cytotoxicity against HCC, and sorafenib treatment could enhance IL12A signals via suppressing AR signals. These results not only help to explain the AR roles in the gender disparity of HCC but also provide a potential new therapy to better suppress HCC via combining sorafenib with NK cell–related immunotherapy. Mol Cancer Ther; 15(4); 731–42. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-15-0706
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Abstract PR02: The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Research Vol. 14, No. 4_Supplement ( 2016-04-01), p. PR02-PR02
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 14, No. 4_Supplement ( 2016-04-01), p. PR02-PR02
    Abstract: It is unclear if regenerative capacity can be dissociated from cancer risk, a question that is highly relevant for liver carcinogenesis. Frequent SWI/SNF and Arid1a loss-of-function mutations suggest tumor suppressive roles, but the functional impact of these mutations in tissue homeostasis and cancer is unclear. Mice without Arid1a possessed improved healing abilities after an array of injuries. After liver resection, chemical hepatocyte injury, and toxic bile duct injury, Arid1a deficient livers exhibited increased regeneration, reduced tissue damage, and improved organ function. Moreover, global homozygous Arid1a loss potentiated soft tissue healing after ear hole punch and hematopoietic recovery after irradiation. The chromatin state as reprogrammed by Arid1a loss restricted access to promoters by lineage-specific transcription factors that ordinarily suppress cell cycle reentry, thus increasing regeneration after injury. Intriguingly, the homozygous Arid1a deficient state protected mice from chemical injury induced hepatocellular carcinoma (HCC) and extended survival in a MYC-driven hepatoblastoma model. Since Arid1a mutations are most frequently heterozygous in human HCC genome studies, we examined the haploinsufficient state in these mouse models and observed accelerated carcinogenesis and metastasis. Transcriptome analysis identified dysregulated differentiation, proliferation, and metastasis programs. These models show that full deletion of Arid1a can enhance mammalian regeneration without increasing cancer risk, but that Arid1a’s tumor suppressor functions are highly sensitive to dose. This abstract is also presented as Poster A16. Citation Format: Xuxu Sun, Sam Wang, Thomas Maples, Lin Li, Liem Nguyen, Jen-Chieh Chuang, Mahsa Sorouri, Shuyuan Zhang, Linwei Wu, Cemre Celen, Hao Zhu. The SWI/SNF component Arid1a regulates regenerative capacity and carcinogenesis in a dose-dependent fashion. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr PR02.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.DEVBIOLCA15-PR02
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2097884-4
    SSG: 12
    Location Call Number Limitation Availability
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