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. 2025 Oct 9;38(6):175.
doi: 10.1007/s13577-025-01308-6.

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

Yusuke Yoshimura  1   2 , Keiichi Yoshida  3 , Yukiko Matsuoka  3 , Satoru Sasagawa  4 , Noriko Nagamine  1 , Yoji Kukita  5 , Ryota Miyamoto  1   2 , Rie Suzuki  1   2 , Hironari Tamiya  1   2 , Shigeki Kakunaga  1   2 , Toshinari Yagi  1 , Takuya Terakawa  6 , Yuma Tada  6 , Takafumi Yokota  6 , Jun Ishikawa  6 , Sho Nakai  2 , Yoshinori Imura  2 , Seiji Okada  2 , Ken-Ichi Yoshida  7 , Satoshi Takenaka  1   2 , Toru Wakamatsu  8   9
Affiliations

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

Yusuke Yoshimura et al. Hum Cell. .

Abstract

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.

Keywords: Histiocytic sarcoma; Organoid; Sonic Hedgehog; YAP1.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Ethical approval and informed consent to participate: The use of clinical materials for this study was approved by the Ethics Committee of Osaka International Cancer Institute (approval number: 1710059174-12), and all procedures were conducted in accordance with institutional and national ethical guidelines. Written informed consent was obtained from the patient.

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