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Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties

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  • Mizuho Nakayama

    (Division of Genetics, Cancer Research Institute, Kanazawa University
    WPI Nano Life Science Institute, Kanazawa University)

  • Chang Pyo Hong

    (Theragen Etex Bio Institute)

  • Hiroko Oshima

    (Division of Genetics, Cancer Research Institute, Kanazawa University
    WPI Nano Life Science Institute, Kanazawa University)

  • Eri Sakai

    (Division of Genetics, Cancer Research Institute, Kanazawa University)

  • Seong-Jin Kim

    (Theragen Etex Bio Institute
    Precision Medicine Research Center, Advanced Institute of Convergence Technology and Department of Transdisciplinary Studies, Seoul National University)

  • Masanobu Oshima

    (Division of Genetics, Cancer Research Institute, Kanazawa University
    WPI Nano Life Science Institute, Kanazawa University)

Abstract

Missense-type mutant p53 plays a tumor-promoting role through gain-of-function (GOF) mechanism. In addition, the loss of wild-type TP53 through loss of heterozygosity (LOH) is widely found in cancer cells. However, malignant progression induced by cooperation of TP53 GOF mutation and LOH remains poorly understood. Here, we show that mouse intestinal tumors carrying Trp53 GOF mutation with LOH (AKTPM/LOH) are enriched in metastatic lesions when heterozygous Trp53 mutant cells (AKTP+/M) are transplanted. We show that Trp53 LOH is required for dormant cell survival and clonal expansion of cancer cells. Moreover, AKTPM/LOH cells show an increased in vivo tumor-initiating ability compared with AKTPNull and AKTP+/M cells. RNAseq analyses reveal that inflammatory and growth factor/MAPK pathways are specifically activated in AKTPM/LOH cells, while the stem cell signature is upregulated in both AKTPM/LOH and AKTPNull cells. These results indicate that TP53/Trp53 LOH promotes TP53/Trp53 GOF mutation-driven metastasis through the activation of distinct pathway combination.

Suggested Citation

  • Mizuho Nakayama & Chang Pyo Hong & Hiroko Oshima & Eri Sakai & Seong-Jin Kim & Masanobu Oshima, 2020. "Loss of wild-type p53 promotes mutant p53-driven metastasis through acquisition of survival and tumor-initiating properties," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16245-1
    DOI: 10.1038/s41467-020-16245-1
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    Cited by:

    1. Nicholas Light & Mehdi Layeghifard & Ayush Attery & Vallijah Subasri & Matthew Zatzman & Nathaniel D. Anderson & Rupal Hatkar & Sasha Blay & David Chen & Ana Novokmet & Fabio Fuligni & James Tran & Ri, 2023. "Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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