Metastasis occurs in the majority of pancreatic ductal adenocarcinoma (PDAC) patients at diagnosis or following resection. Patients with liver metastasis and those with lung metastasis have significantly different prognosis. Here, we sought to understand how cancer-associated fibroblasts (CAFs) play roles in the development of organ-specific metastasis. PDAC tumor cell lines established from the primary tumors with liver and lung metastasis potentials, respectively, in Kras/p53 mutation conditional knock-in (KPC) mice were co-cultured with matched CAFs or mouse mesenchymal stem cells. CAFs were isolated from metastases and subjected to DNA methylation and whole transcriptomic RNA sequencing analysis. The ability of mouse PDAC tumor cell lines in developing liver or lung-specific metastases was demonstrated in orthotopic models. Tumor cells associated with liver metastasis potential, but not those associated with lung metastasis potential, induced the methylation of metabolism genes including NQO1 and ALDH1a3 and subsequent downregulated mRNA expression of a broader group of metabolism genes in CAFs. DNA methylation and downregulation of metabolism genes in CAFs in liver metastasis, but not those in lung metastasis, appeared to be regulated by DNA methyltransferase. Tumor cells associated with liver metastasis potential, but not those associated with lung metastasis potential, induce inflammatory CAF (iCAF) signatures. CAFs from liver metastasis demonstrated a more homogenous iCAF phenotype, whereas CAFs from lung metastasis maintained the heterogeneity. PDAC with organ-specific metastatic potentials has different capacities in inducing methylation of metabolism genes in CAFs, modulating CAF phenotypes, and resulting in different levels of heterogeneity of CAFs in different metastatic niches.

中文翻译：

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癌症相关的成纤维细胞异质性与胰腺导管腺癌的器官特异性转移有关

大多数胰腺导管腺癌 (PDAC) 患者在诊断时或切除后都会发生转移。肝转移患者和肺转移患者的预后有显着差异。在这里，我们试图了解癌症相关成纤维细胞 (CAF) 如何在器官特异性转移的发展中发挥作用。在 Kras/p53 突变条件敲入 (KPC) 小鼠中分别从具有肝和肺转移潜力的原发性肿瘤建立的 PDAC 肿瘤细胞系与匹配的 CAF 或小鼠间充质干细胞共培养。从转移灶中分离出 CAF，并进行 DNA 甲基化和全转录组 RNA 测序分析。在原位模型中证实了小鼠 PDAC 肿瘤细胞系发展肝或肺特异性转移的能力。与肝转移潜能相关但与肺转移潜能无关的肿瘤细胞诱导包括 NQO1 和 ALDH1a3 在内的代谢基因甲基化，随后下调 CAF 中更广泛的代谢基因组的 mRNA 表达。肝转移中 CAF 中的 DNA 甲基化和代谢基因的下调，但不是肺转移中的，似乎受 DNA 甲基转移酶的调节。与肝转移潜能相关但与肺转移潜能无关的肿瘤细胞诱导炎症性 CAF (iCAF) 特征。来自肝转移的 CAF 表现出更同质的 iCAF 表型，而来自肺转移的 CAF 保持了异质性。