A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes

Jorge De La Rosa, Julia Weber, Mathias Josef Friedrich, Yilong Li, Lena Rad, Hannes Ponstingl, Qi Liang, Sandra Bernaldo De Quirós, Imran Noorani, Emmanouil Metzakopian, Alexander Strong, Meng Amy Li, Aurora Astudillo, María Teresa Fernández-García, María Soledad Fernández-García, Gary J. Hoffman, Rocío Fuente, George S. Vassiliou, Roland Rad, Carlos López-Otín & 2 others Allan Bradley, Juan Cadiñanos

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    Abstract

    The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.

    Original languageEnglish
    Pages (from-to)730-741
    Number of pages12
    JournalNature Genetics
    Volume49
    Issue number5
    DOIs
    Publication statusPublished - 1 May 2017

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    Beauty
    Tumor Suppressor Genes
    Mutagenesis
    Neoplasms
    Genome
    Haploinsufficiency
    Insertional Mutagenesis
    Autophagy
    Genes
    Prostate
    Prostatic Neoplasms
    Breast Neoplasms
    Skin

    Cite this

    De La Rosa, J., Weber, J., Friedrich, M. J., Li, Y., Rad, L., Ponstingl, H., ... Cadiñanos, J. (2017). A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes. Nature Genetics, 49(5), 730-741. https://doi.org/10.1038/ng.3817
    De La Rosa, Jorge ; Weber, Julia ; Friedrich, Mathias Josef ; Li, Yilong ; Rad, Lena ; Ponstingl, Hannes ; Liang, Qi ; De Quirós, Sandra Bernaldo ; Noorani, Imran ; Metzakopian, Emmanouil ; Strong, Alexander ; Li, Meng Amy ; Astudillo, Aurora ; Fernández-García, María Teresa ; Fernández-García, María Soledad ; Hoffman, Gary J. ; Fuente, Rocío ; Vassiliou, George S. ; Rad, Roland ; López-Otín, Carlos ; Bradley, Allan ; Cadiñanos, Juan. / A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes. In: Nature Genetics. 2017 ; Vol. 49, No. 5. pp. 730-741.
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    abstract = "The overwhelming number of genetic alterations identified through cancer genome sequencing requires complementary approaches to interpret their significance and interactions. Here we developed a novel whole-body insertional mutagenesis screen in mice, which was designed for the discovery of Pten-cooperating tumor suppressors. Toward this aim, we coupled mobilization of a single-copy inactivating Sleeping Beauty transposon to Pten disruption within the same genome. The analysis of 278 transposition-induced prostate, breast and skin tumors detected tissue-specific and shared data sets of known and candidate genes involved in cancer. We validated ZBTB20, CELF2, PARD3, AKAP13 and WAC, which were identified by our screens in multiple cancer types, as new tumor suppressor genes in prostate cancer. We demonstrated their synergy with PTEN in preventing invasion in vitro and confirmed their clinical relevance. Further characterization of Wac in vivo showed obligate haploinsufficiency for this gene (which encodes an autophagy-regulating factor) in a Pten-deficient context. Our study identified complex PTEN-cooperating tumor suppressor networks in different cancer types, with potential clinical implications.",
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    De La Rosa, J, Weber, J, Friedrich, MJ, Li, Y, Rad, L, Ponstingl, H, Liang, Q, De Quirós, SB, Noorani, I, Metzakopian, E, Strong, A, Li, MA, Astudillo, A, Fernández-García, MT, Fernández-García, MS, Hoffman, GJ, Fuente, R, Vassiliou, GS, Rad, R, López-Otín, C, Bradley, A & Cadiñanos, J 2017, 'A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes' Nature Genetics, vol. 49, no. 5, pp. 730-741. https://doi.org/10.1038/ng.3817

    A single-copy Sleeping Beauty transposon mutagenesis screen identifies new PTEN-cooperating tumor suppressor genes. / De La Rosa, Jorge; Weber, Julia; Friedrich, Mathias Josef; Li, Yilong; Rad, Lena; Ponstingl, Hannes; Liang, Qi; De Quirós, Sandra Bernaldo; Noorani, Imran; Metzakopian, Emmanouil; Strong, Alexander; Li, Meng Amy; Astudillo, Aurora; Fernández-García, María Teresa; Fernández-García, María Soledad; Hoffman, Gary J.; Fuente, Rocío; Vassiliou, George S.; Rad, Roland; López-Otín, Carlos; Bradley, Allan; Cadiñanos, Juan.

    In: Nature Genetics, Vol. 49, No. 5, 01.05.2017, p. 730-741.

    Research output: Contribution to journalArticle

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    AU - Rad, Lena

    AU - Ponstingl, Hannes

    AU - Liang, Qi

    AU - De Quirós, Sandra Bernaldo

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    AU - Metzakopian, Emmanouil

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