Cancer-associated fibroblast heterogeneity is associated with organ-specific metastasis in pancreatic ductal adenocarcinoma

Journal of Hematology & Oncology

Qian Xiao¹  Wei Gong²  Lei Zheng³  Xingyi Pan⁴  Guanglan Mo⁴  Mengwen Zhang⁴  Kenji Fujiwara⁴  Jiaojiao Zhou⁵ 

[1] The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 488, 21287, Baltimore, MD, USA;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 488, 21287, Baltimore, MD, USA;Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Surgery, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 488, 21287, Baltimore, MD, USA;Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA;The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 488, 21287, Baltimore, MD, USA;The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA;The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans Street, CRB1 Room 488, 21287, Baltimore, MD, USA;The Second Affiliated Hospital of the Zhejiang University, 88 Jie-Fang Rd, 310009, Hangzhou, China;

关键词: DNA methylation;    Cancer-associated fibroblast;    Heterogeneity;    Organ-specific metastasis;    Pancreatic cancer;   

DOI  :  10.1186/s13045-021-01203-1

来源: Springer

【 摘 要 】

BackgroundMetastasis 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.MethodsPDAC 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.ResultsThe 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.ConclusionsPDAC 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.

【 授权许可】

CC BY