Pancreatic cancer cells render tumor-associated macrophages metabolically reprogrammed by a GARP and DNA methylation-mediated mechanism  

作　　者：Mengwen Zhang Xingyi Pan Kenji Fujiwara Noelle Jurcak Stephen Muth Jiaojiao Zhou Qian Xiao Anqi Li Xu Che Zihai Li Lei Zheng 

机构地区：[1]Department of Oncology,Johns Hopkins University School of Medicine,Baltimore,MD,21287,USA [2]The Sidney Kimmel Cancer Center,Johns Hopkins University School of Medicine,Baltimore,MD,21287,USA [3]The Pancreatic Cancer Precision Medicine Center of Excellence Program,Johns Hopkins University School of Medicine,Baltimore,MD,21287,USA [4]The Cellular and Molecular Medicine Graduate Program,Johns Hopkins University School of Medicine,Baltimore,MD,21287,USA [5]Pelotonia Institute for Immune-Oncology,The Ohio State University Comprehensive Cancer Center,Columbus,OH,43210,USA [6]Department of Surgery,Johns Hopkins University School of Medicine,Baltimore,MD,21287,USA [7]The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China [8]Department of Surgery,Sada Hospital,Fukuoka,Japan [9]Cancer Hospital,Chinese Academy of Medical Sciences,Shenzhen,China

出　　处：《Signal Transduction and Targeted Therapy》2021年第11期3348-3365,共18页信号转导与靶向治疗（英文）

基　　金：L.Z.was supported by NIH grant R01 CA169702;NIH grant R01 CA197296;the Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins,Sidney Kimmel Comprehensive Cancer Center Grant P30 CA006973;K.F.was supported by a JSPS Overseas Research Fellowship from the Japan Society for the Promotion of Science.Z.L.is supported by multiple NIH grants(R01 AI077283,P01 CA186866,R01 CA199419,and R01 CA213290).

摘　　要：How tumor-associated macrophages transit from a predominant antitumor M1-like phenotype to a protumoral M2-like phenotype during the development of pancreatic ductal adenocarcinoma (PDA) remains to be elucidated. We thus conducted a study by employing a PDA-macrophage co-culture system, an “orthotopic” PDA syngeneic mouse model, and human PDA specimens, together with macrophages derived from GARP knockout mice and multiple analytic tools including whole-genome RNA sequencing, DNA methylation arrays, multiplex immunohistochemistry, metabolism measurement, and invasion/metastasis assessment. Our study showed that PDA tumor cells, through direct cell–cell contact, induce DNA methylation and downregulation of a panel of glucose metabolism and OXPHOS genes selectively in M1-like macrophages, leading to a suppressed glucose metabolic status in M1-like but not in M2-like macrophages. Following the interaction with PDA tumor cells, M1-like macrophages are reprogrammed phenotypically to M2-like macrophages. The interaction between M1-like macrophages and PDA cells is mediated by GARP and integrin αV/β8, respectively. Blocking either GARP or integrin would suppress tumor-induced DNA methylation in Nqo-1 gene and the reprogramming of M1-like macrophages. Glucose-response genes such as Il-10 are subsequently activated in tumor-educated M1-like macrophages. Partly through Il-10 and its receptor Il-10R on tumor cells, M1-like macrophages functionally acquire a pro-cancerous capability. Both exogenous M1-like and M2-like macrophages promote metastasis in a mouse model of PDA while such a role of M1-like macrophages is dependent on DNA methylation. Our results suggest that PDA cells are able to reprogram M1-like macrophages metabolically and functionally through a GARP-dependent and DNA methylation-mediated mechanism to adopt a pro-cancerous fate.

关 键 词：METABOLISM METASTASIS MEDIATED 

分 类 号：R735.9[医药卫生—肿瘤]