Scholarlink

Background &amp; aims <p>The mechanisms of peritoneal dissemination in pancreatic ductal adenocarcinoma (PDAC) remain unclear partly owing to the lack of patient-derived models that recapitulate this process. This study aimed to establish an orthotopic model of PDAC peritoneal dissemination and to uncover the transcriptional and regulatory programs underlying this process.</p> Methods <p>Organoids were established from primary pancreatic tumors and malignant effusions of patients with PDAC and orthotopically transplanted into the pancreas of immunodeficient mice to generate patient-derived orthotopic xenograft (PDOX) models. Subsequently, the organoids were rederived from pancreatic and peritoneal lesions of a representative model (PDOX12) and orthotopically reimplanted to assess the dissemination capacity. Single-nucleus RNA sequencing (snRNA-seq) and single-cell ATAC sequencing (scATAC-seq) were performed to analyze the tumors from these models.</p> Results <p>The organoids that were derived from malignant effusions reproducibly generated peritoneal metastases after orthotopic implantation. To dissect this process more precisely, we focused on one representative model (PDOX12) and rederived organoids from its pancreatic and peritoneal lesions. These organoids generated matched PDOX models that differed only in dissemination potential when reimplanted orthotopically. The results of snRNA-seq revealed a distinct subpopulation enriched in the high-dissemination model, which was characterized by the coordinated activation of genes involved in cytoskeletal dynamics, extracellular matrix remodeling, and plasticity-related signaling—suggesting a dissemination-primed state. Integration with scATAC-seq identified STAT3, SMAD3, and SOX2 as potential upstream regulators of this gene program.</p> Conclusions <p>This study established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Patient-derived orthotopic xenograft models recapitulate the peritoneal dissemination of pancreatic cancer and delineate its transcriptional and regulatory programs

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月11日

查看全文
  • Takaaki Furukawa,
  • Kohei Kumegawa,
  • Kenichi Miyata,
  • Manabu Takamatsu,
  • Asumi Iesato,
  • Sumito Saeki,
  • Liying Yang,
  • Chikako Shibata,
  • Tomoko Takahara,
  • Kaoru Masuda,
  • Takafumi Mie,
  • Takeshi Okamoto,
  • Tsuyoshi Takeda,
  • Takashi Sasaki,
  • Masato Ozaka,
  • Miwa Tanaka,
  • Shunji Takahashi,
  • Tetsuo Noda,
  • Ryoji Yao,
  • Naoki Sasahira,
  • Reo Maruyama

摘要

Background & aims

The mechanisms of peritoneal dissemination in pancreatic ductal adenocarcinoma (PDAC) remain unclear partly owing to the lack of patient-derived models that recapitulate this process. This study aimed to establish an orthotopic model of PDAC peritoneal dissemination and to uncover the transcriptional and regulatory programs underlying this process.

Methods

Organoids were established from primary pancreatic tumors and malignant effusions of patients with PDAC and orthotopically transplanted into the pancreas of immunodeficient mice to generate patient-derived orthotopic xenograft (PDOX) models. Subsequently, the organoids were rederived from pancreatic and peritoneal lesions of a representative model (PDOX12) and orthotopically reimplanted to assess the dissemination capacity. Single-nucleus RNA sequencing (snRNA-seq) and single-cell ATAC sequencing (scATAC-seq) were performed to analyze the tumors from these models.

Results

The organoids that were derived from malignant effusions reproducibly generated peritoneal metastases after orthotopic implantation. To dissect this process more precisely, we focused on one representative model (PDOX12) and rederived organoids from its pancreatic and peritoneal lesions. These organoids generated matched PDOX models that differed only in dissemination potential when reimplanted orthotopically. The results of snRNA-seq revealed a distinct subpopulation enriched in the high-dissemination model, which was characterized by the coordinated activation of genes involved in cytoskeletal dynamics, extracellular matrix remodeling, and plasticity-related signaling—suggesting a dissemination-primed state. Integration with scATAC-seq identified STAT3, SMAD3, and SOX2 as potential upstream regulators of this gene program.

Conclusions

This study established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.