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DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency

Author

Listed:
  • Jumpei Taguchi

    (The University of Tokyo, Minoto-ku)

  • Hirofumi Shibata

    (Kyoto University, Sakyo-ku
    Gifu University Graduate School of Medicine)

  • Mio Kabata

    (Kyoto University, Sakyo-ku)

  • Masaki Kato

    (Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako-shi
    RIKEN Center for Integrative Medical Sciences)

  • Kei Fukuda

    (Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako-shi)

  • Akito Tanaka

    (Kyoto University, Sakyo-ku)

  • Sho Ohta

    (The University of Tokyo, Minoto-ku)

  • Tomoyo Ukai

    (The University of Tokyo, Minoto-ku)

  • Kanae Mitsunaga

    (Kyoto University, Sakyo-ku)

  • Yosuke Yamada

    (Kyoto University, Sakyo-ku
    Kyoto University Hospital)

  • So I Nagaoka

    (Kyoto University, Yoshida-Konoe-cho, Sakyo-ku
    Nara Medical University)

  • Sho Yamazawa

    (The University of Tokyo)

  • Kotaro Ohnishi

    (Kyoto University, Sakyo-ku
    Gifu University Graduate School of Medicine)

  • Knut Woltjen

    (Kyoto University, Sakyo-ku)

  • Tetsuo Ushiku

    (The University of Tokyo)

  • Manabu Ozawa

    (The University of Tokyo)

  • Mitinori Saitou

    (Kyoto University, Sakyo-ku
    Kyoto University, Yoshida-Konoe-cho, Sakyo-ku
    Kyoto University, Yoshida-Konoe-cho, Sakyo-ku)

  • Yoichi Shinkai

    (Cellular Memory Laboratory, RIKEN Cluster for Pioneering Research, Wako-shi)

  • Takuya Yamamoto

    (Kyoto University, Sakyo-ku
    Kyoto University, Yoshida-Konoe-cho, Sakyo-ku
    Medical-risk Avoidance Based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP)
    AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku)

  • Yasuhiro Yamada

    (The University of Tokyo, Minoto-ku
    AMED-CREST, AMED 1-7-1 Otemachi, Chiyodaku)

Abstract

In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors.

Suggested Citation

  • Jumpei Taguchi & Hirofumi Shibata & Mio Kabata & Masaki Kato & Kei Fukuda & Akito Tanaka & Sho Ohta & Tomoyo Ukai & Kanae Mitsunaga & Yosuke Yamada & So I Nagaoka & Sho Yamazawa & Kotaro Ohnishi & Knu, 2021. "DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25249-4
    DOI: 10.1038/s41467-021-25249-4
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