Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, 06120 Halle, Germany.
Institute of Pathology, Section for Experimental Pathology, Martin-Luther-University Halle-Wittenberg, University Medical Center Halle, 06120 Halle, Germany.
Cells. 2022 Aug 19;11(16):2583. doi: 10.3390/cells11162583.
Cancer-associated fibroblasts (CAFs) play a major role in the progression and drug resistance of pancreatic cancer. Recent studies suggest that CAFs exhibit functional heterogeneity and distinct transcriptomic signatures in pancreatic cancer. Pancreatic fibroblasts also form an integral component in pancreatic diseases such as chronic pancreatitis named disease-associated fibroblasts (DAFs). However, intra-tumoral heterogeneity of CAFs in pancreatic cancer patients and their pivotal role in cancer-related mechanisms have not been fully elucidated. Further, it has not been elucidated whether CAF subtypes identified in pancreatic cancer also exist in chronic pancreatitis. In this study, we used primary isolated fibroblasts from pancreatic cancer and chronic pancreatitis patients using the outgrowth method. Single-cell RNA sequencing (scRNA-seq) was performed, and bioinformatics analysis identified highly variable genes, including factors associated with overall survival of pancreatic cancer patients. The majority of highly variable genes are involved in the cell cycle. Instead of previously classified myofibroblastic (myCAFs), inflammatory (iCAFs), and antigen-presenting (ap) CAFs, we identified a myCAFs-like subtype in all cases. Most interestingly, after cell cycle regression, we observed 135 highly variable genes commonly identified in chronic pancreatitis and pancreatic cancer patients. This study is the first to conduct scRNAseq and bioinformatics analyses to compare CAFs/DAFs from both chronic pancreatitis and pancreatic cancer patients. Further studies are required to select and identify stromal factors in DAFs from chronic pancreatitis cases, which are commonly expressed also in CAFs potentially contributing to pancreatic cancer development.
癌症相关成纤维细胞 (CAFs) 在胰腺癌的进展和耐药性中起主要作用。最近的研究表明，CAFs 在胰腺癌中表现出功能异质性和独特的转录组特征。胰腺成纤维细胞也是慢性胰腺炎等胰腺疾病中不可或缺的组成部分，称为疾病相关成纤维细胞 (DAFs)。然而，胰腺癌患者中 CAFs 的肿瘤内异质性及其在癌症相关机制中的关键作用尚未完全阐明。此外，CAF 亚型在胰腺癌中是否也存在于慢性胰腺炎中尚不清楚。在这项研究中，我们使用原代分离的胰腺癌细胞和慢性胰腺炎患者的成纤维细胞，采用外生法进行单细胞 RNA 测序 (scRNA-seq)，并进行生物信息学分析，鉴定出高度可变基因，包括与胰腺癌患者总生存率相关的因素。大多数高度可变基因参与细胞周期。除了先前分类的肌成纤维细胞 (myCAFs)、炎症 (iCAFs) 和抗原呈递 (ap) CAFs 外，我们在所有病例中都鉴定出一种类似 myCAFs 的亚型。最有趣的是，在细胞周期回归后，我们观察到在慢性胰腺炎和胰腺癌患者中共同鉴定出 135 个高度可变基因。这项研究是首次对慢性胰腺炎和胰腺癌患者的 CAFs/DAFs 进行 scRNAseq 和生物信息学分析比较。需要进一步研究以选择和鉴定慢性胰腺炎病例中 DAFs 的基质因子，这些因子在 CAFs 中也普遍表达，可能有助于胰腺癌的发展。
