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<p>Biliary tract carcinoma (BTC) is a malignancy with poor prognosis. Current molecular targeted therapies benefit only a limited subset of patients, underscoring the need for novel approaches, such as combining DNA-damaging chemoradiotherapy with an immune checkpoint inhibitor. Although cellular responses following chemoradiotherapy-induced DNA damage are essential, they remain poorly understood in the context of three-dimensional tumor structures. This study aimed to investigate the effects of ionizing radiation, a DNA-damaging cancer therapy, on patient-derived BTC organoids. DNA repair and gene expression regulation was integrally examined by immunofluorescence and RNA-Seq analysis following 10&#xa0;Gy of X-rays. X-ray irradiation caused significant morphological changes. In addition, X-ray irradiation upregulated extracellular matrix-related gene expression as revealed by RNA sequencing. DNA damage response analysis indicated that non-homologous end joining was the primary repair pathway in patient-derived BTC organoids. Moreover, X-ray irradiation activated immune-related pathways, such as cGAS/STING, RIG-I/MDA-5, and JAK/STAT, suggesting potential immune activation following radiotherapy. Our study revealed that DNA damage response altered the tumor structure and modulated the expression of multiple genes, including extracellular matrix- and immune-related genes. Studies using in vitro organoid models can be useful for investigating three-dimensional cellular responses after DNA-damaging cancer therapies, such as chemoradiotherapy.</p>

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Comprehensive analysis of DNA repair, morphological remodeling and immune-gene expression in patient-derived biliary tract carcinoma organoids following ionizing radiation

  • 期刊论文

  • 发表日期：

    2026年2月11日

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  • Ken Okuda,
  • Shunji Haruna,
  • Toshihide Muramatsu,
  • Kohei Tateno,
  • Mayu Isono,
  • Kunihiro Miyazaki,
  • Takahiro Oike,
  • Haruka Okami,
  • Takehiko Yokobori,
  • Keiji Suzuki,
  • Kensuke Otsuka,
  • Akiko Takahashi,
  • Yoshimasa Saito,
  • Atsushi Shibata

摘要

Biliary tract carcinoma (BTC) is a malignancy with poor prognosis. Current molecular targeted therapies benefit only a limited subset of patients, underscoring the need for novel approaches, such as combining DNA-damaging chemoradiotherapy with an immune checkpoint inhibitor. Although cellular responses following chemoradiotherapy-induced DNA damage are essential, they remain poorly understood in the context of three-dimensional tumor structures. This study aimed to investigate the effects of ionizing radiation, a DNA-damaging cancer therapy, on patient-derived BTC organoids. DNA repair and gene expression regulation was integrally examined by immunofluorescence and RNA-Seq analysis following 10 Gy of X-rays. X-ray irradiation caused significant morphological changes. In addition, X-ray irradiation upregulated extracellular matrix-related gene expression as revealed by RNA sequencing. DNA damage response analysis indicated that non-homologous end joining was the primary repair pathway in patient-derived BTC organoids. Moreover, X-ray irradiation activated immune-related pathways, such as cGAS/STING, RIG-I/MDA-5, and JAK/STAT, suggesting potential immune activation following radiotherapy. Our study revealed that DNA damage response altered the tumor structure and modulated the expression of multiple genes, including extracellular matrix- and immune-related genes. Studies using in vitro organoid models can be useful for investigating three-dimensional cellular responses after DNA-damaging cancer therapies, such as chemoradiotherapy.