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

作者机构：Department of OncologyJohns Hopkins University School of MedicineBaltimoreMD21287USA The Sidney Kimmel Cancer CenterJohns Hopkins University School of MedicineBaltimoreMD21287USA The Pancreatic Cancer Precision Medicine Center of Excellence ProgramJohns Hopkins University School of MedicineBaltimoreMD21287USA The Cellular and Molecular Medicine Graduate ProgramJohns Hopkins University School of MedicineBaltimoreMD21287USA Pelotonia Institute for Immune-OncologyThe Ohio State University Comprehensive Cancer CenterColumbusOH43210USA Department of SurgeryJohns Hopkins University School of MedicineBaltimoreMD21287USA The Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina Department of SurgerySada HospitalFukuokaJapan Cancer HospitalChinese Academy of Medical SciencesShenzhenChina 

出 版 物：《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗（英文）)

年 卷 期：2021年第6卷第11期

页      面：3348-3365页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

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) 

主　　题：metabolism metastasis mediated 

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.