The scRNA-sequencing landscape of pancreatic ductal adenocarcinoma revealed distinct cell populations associated with tumor initiation and progression  

作　　者：Ying Wang Zhouliang Bian Lichao Xu Guangye Du Zihao Qi Yanjie Zhang Jiang Long Wentao Li 

机构地区：[1]Department of Interventional Radiology,Department of Medical Oncology,Fudan University Shanghai Cancer Center,Shanghai 200032,China [2]Department of Oncology,Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 201900,China [3]Shanghai Institute of Precision Medicine,Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200125,China [4]Department of Pathology,Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 201900,China [5]Department of Pancreatic Surgery,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China [6]Shanghai Key Laboratory of Pancreatic Disease,Institute of Pancreatic Disease,Shanghai Jiao Tong University School of Medicine,Shanghai 200080,China

出　　处：《Genes & Diseases》2025年第3期447-462,共16页基因与疾病(英文)

基　　金：supported by grants from the National Natural Science Foundation of China(No.82272095 to W.L.,82072638 to Y.Z.and 82002537 to Z.Q.);supported by grants from Zhangjiang National Innovation Demonstration Zone(Shanghai,China)(No.ZJ2021-ZD-007 to W.L.);the Biobank Program of Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine(Shanghai,China)(No.YBKB202217 to Y.Z.).

摘　　要：Pancreatic ductal adenocarcinoma (PDAC) stands as a formidable malignancy characterized by its profound lethality. The comprehensive analysis of the transcriptional landscape holds immense significance in understanding PDAC development and exploring noveltreatment strategies. However, due to the firm consistency of pancreatic cancer samples,the dissociation of single cells and subsequent sequencing can be challenging. Here, we performed single-cell RNA sequencing (scRNA-seq) on 8 PDAC patients with different lymph node metastasis status. We first identified the crucial role of MMP1 in the transition from normalpancreatic cells to cancer cells. The knockdown of MMP1 in pancreatic cancer cell linesdecreased the expression of ductal markers such as SOX9 while the overexpression of MMP1in hTERT-HPNE increased the expression of ductal markers, suggesting its function of maintaining ductal identity. Secondly, we found a S100A2^(+) tumor subset which fueled lymph nodemetastasis in PDAC. The knockdown of S100A2 significantly reduced the motility of pancreaticcancer cell lines in both wound healing and transwell migration assays. While overexpression ofS100A2 led to increased migratory capability. Moreover, overexpression of S100A2 in KPC1199,a mouse pancreatic cancer cell line, caused a larger tumor burden in a hemi-spleen injectionmodel of liver metastasis. In addition, epithelial-mesenchymal transition-related genes weredecreased by S100A2 knockdown revealed by bulk RNA sequencing. We also identified severalpivotal contributors to the pro-tumor microenvironment, notably OMD^(+) fibroblast and CCL2^(+)macrophage. As a result, our study provides valuable insights for early detection of PDACand promising therapeutic targets for combatting lymph node metastasis.

关 键 词：Acinar-to-ductal metaplasia Lymph node metastasis Pancreatic ductal adenocarcinoma Single-cell RNA sequencing Tumor microenvironment 

分 类 号：R735.9[医药卫生—肿瘤]