PO.TB03.04 · 肿瘤生物学

患者来源的原位异种移植模型重现胰腺癌的腹膜播散并勾勒其转录组、调控和空间程序

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

编号 2125 展板 23 时间 4/20 09:00–12:00 区域 Section 27 主讲 Takaaki Furukawa, MD

分会场 Characterization of Metastases by Imaging and Profiling

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Takaaki Furukawa¹, Kohei Kumegawa¹, manabu takamatsu², Kenichi Miyata¹, Sumito Saeki¹, Chikako Shibata¹, Takafumi Mie³, Takeshi Okamoto³, Tsuyoshi Takeda³, Takashi Sasaki³, Masato Ozaka³, Miwa Tanaka¹, Shunji Takahashi⁴, Tetsuo Noda⁵, Yao Ryoji⁶, Naoki Sasahira³, Reo Maruyama¹

¹Division of Cancer Epigenomics, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan,²Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan,³Division of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan,⁴The Cancer Institute Hospital of JFCR, Tokyo, Japan,⁵Director, Japanese Fndn. for Cancer Res. Cancer Institute, Tokyo, Japan,⁶The JFCR Cancer Institute, Tokyo, Japan

摘要 Abstract

中文摘要

背景：胰腺导管腺癌（PDAC）腹膜播散的机制仍不明确，部分原因在于缺乏能够重现该过程的患者来源模型。本研究旨在建立PDAC腹膜播散的原位模型，并揭示支撑该过程的转录和调控程序。方法：从PDAC患者的原发胰腺肿瘤和恶性积液中建立类器官，并原位移植入免疫缺陷小鼠的胰腺中，以生成患者来源的原位异种移植（PDOX）模型。随后，从一个代表性模型（PDOX12）的胰腺和腹膜病灶中重新衍生类器官，并原位再植入以评估播散能力。进行单核RNA测序（snRNA-seq）、单细胞ATAC测序（scATAC-seq）和空间转录组分析，以分析这些模型的肿瘤。结果：源自恶性积液的类器官在原位植入后可重复地产生腹膜转移。为更精确地剖析该过程，我们聚焦于一个代表性模型（PDOX12），并从其胰腺和腹膜病灶中重新衍生类器官（分别为PDXO12P和PDXO12A）。这些类器官在原位再植入时生成了仅在播散潜能上有差异的匹配PDOX模型。snRNA-seq的结果揭示了一个在高播散模型中富集的独特亚群，提示一种播散预备状态。与scATAC-seq的整合鉴定出该亚群基因程序的潜在上游调控因子。此外，PDOX系统揭示了细胞可塑性。在体外，PDXO12P和PDXO12A类器官表现出几乎无法区分的转录和增殖特征。然而，当置于体内时，它们的潜在差异被揭示：PDXO12A表现出更强的腹膜播散，并伴有明显的转录分化。我们假设这些差异是由肿瘤微环境（TME）的影响所揭示的，并进行了空间转录组分析，以在高播散模型中刻画TME并全面表征成纤维细胞的转录特征。结论：我们建立了能够分离腹膜播散表型并揭示驱动该过程的转录和调控程序的PDOX模型。

查看英文原文 English abstract

BACKGROUND: 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), single-cell ATAC sequencing (scATAC-seq) and spatial transcriptomic analysis 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 (PDXO12P and PDXO12A, respectively). 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, suggesting a dissemination-primed state. Integration with scATAC-seq identified potential upstream regulators of the gene programs in the subpopulation. Furthermore, the cellular plasticity was revealed by the PDOX system. In vitro, PDXO12P and PDXO12A organoids exhibited nearly indistinguishable transcriptional and proliferative profiles. However, their latent differences were unmasked when placed in vivo: PDXO12A demonstrated stronger peritoneal dissemination, accompanied by the clear transcriptional divergence. We hypothesized that these differences were unveiled by the influence of the tumor microenvironment (TME) and performed spatial transcriptomic analysis to profile the TME in the high-dissemination model and comprehensively characterize the transcriptional features of fibroblasts. CONCLUSIONS: We established PDOX models that isolate the peritoneal dissemination phenotype and reveal the transcriptional and regulatory programs driving this process.

利益披露 Disclosure

T. Furukawa, None.. K. Kumegawa, None.. M. takamatsu, None.. K. Miyata, None.. S. Saeki, None.. C. Shibata, None.. T. Mie, None.. T. Okamoto, None.. T. Takeda, None.. T. Sasaki, None.. M. Ozaka, None.. M. Tanaka, None.. N. Sasahira, None.. R. Maruyama, None.

← 返回 AACR 2026 检索