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<p>Histiocytic sarcoma is an extremely rare and aggressive malignant neoplasm characterized by immunophenotypic features of mature histiocytes. The mechanisms underlying its malignant transformation remain poorly understood; consequently, the development of effective therapies remains limited. Resected histiocytic&#xa0;sarcoma specimens were cultured using a modified air–liquid interface organoid method, serially passaged, and xenografted into NOD-scid IL2Rgnull mice. Tumors formed by xenografted organoids retained histological and genetic similarities with the original tumor. Genomic analysis revealed the activation of the Sonic Hedgehog signaling pathway and amplification of Yes-associated protein 1, a key effector of the Hippo pathway. Accordingly, we evaluated the sensitivity of the organoids to the Sonic Hedgehog inhibitor vismodegib and Yes-associated protein 1 inhibitor verteporfin, both of which demonstrated potent in vitro antitumor activity in organoid cultures. This model offers a valuable preclinical platform for investigating the molecular pathology of this rare malignancy and accelerating the development of targeted therapies.</p>

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Establishment of human histiocytic sarcoma organoids dependent on the SHH/YAP pathway

  • 期刊论文

  • 发表日期：

    2025年10月9日

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  • Yusuke Yoshimura,
  • Keiichi Yoshida,
  • Yukiko Matsuoka,
  • Satoru Sasagawa,
  • Noriko Nagamine,
  • Yoji Kukita,
  • Ryota Miyamoto,
  • Rie Suzuki,
  • Hironari Tamiya,
  • Shigeki Kakunaga,
  • Toshinari Yagi,
  • Takuya Terakawa,
  • Yuma Tada,
  • Takafumi Yokota,
  • Jun Ishikawa,
  • Sho Nakai,
  • Yoshinori Imura,
  • Seiji Okada,
  • Ken-ichi Yoshida,
  • Satoshi Takenaka,
  • Toru Wakamatsu

摘要

Histiocytic sarcoma is an extremely rare and aggressive malignant neoplasm characterized by immunophenotypic features of mature histiocytes. The mechanisms underlying its malignant transformation remain poorly understood; consequently, the development of effective therapies remains limited. Resected histiocytic sarcoma specimens were cultured using a modified air–liquid interface organoid method, serially passaged, and xenografted into NOD-scid IL2Rgnull mice. Tumors formed by xenografted organoids retained histological and genetic similarities with the original tumor. Genomic analysis revealed the activation of the Sonic Hedgehog signaling pathway and amplification of Yes-associated protein 1, a key effector of the Hippo pathway. Accordingly, we evaluated the sensitivity of the organoids to the Sonic Hedgehog inhibitor vismodegib and Yes-associated protein 1 inhibitor verteporfin, both of which demonstrated potent in vitro antitumor activity in organoid cultures. This model offers a valuable preclinical platform for investigating the molecular pathology of this rare malignancy and accelerating the development of targeted therapies.