期刊
SIGNAL TRANSDUCTION AND TARGETED THERAPY
卷 6, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41392-021-00769-z
关键词
-
资金
- NIH [R01 CA169702, R01 CA197296, R01 AI077283, P01 CA186866, R01 CA199419, R01 CA213290]
- Viragh Foundation
- Skip Viragh Pancreatic Cancer Center at Johns Hopkins
- Sidney Kimmel Comprehensive Cancer Center Grant [P30 CA006973]
- Japan Society for the Promotion of Science
The study revealed that pancreatic ductal adenocarcinoma (PDA) tumor cells induce DNA methylation and downregulation of glucose metabolism genes selectively in M1-like macrophages, leading to their phenotypic reprogramming into M2-like macrophages. This process is mediated by GARP and integrin alpha V/beta 8 and results in the acquisition of pro-cancerous capabilities by M1-like macrophages through Il-10 activation. The research suggests that PDA cells can reprogram M1-like macrophages metabolically and functionally through DNA methylation to adopt a pro-cancerous fate.
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 alpha V/beta 8, 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.
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