1. Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages.
- Author
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Kemp SB, Steele NG, Carpenter ES, Donahue KL, Bushnell GG, Morris AH, The S, Orbach SM, Sirihorachai VR, Nwosu ZC, Espinoza C, Lima F, Brown K, Girgis AA, Gunchick V, Zhang Y, Lyssiotis CA, Frankel TL, Bednar F, Rao A, Sahai V, Shea LD, Crawford HC, and Pasca di Magliano M
- Subjects
- Adult, Animals, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Carrier Proteins, Complement C1q, Female, Gene Expression genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Macrophages metabolism, Male, Membrane Glycoproteins metabolism, Mice, Mice, Inbred C57BL, Mitochondrial Proteins, Pancreatic Neoplasms blood, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Receptors, Complement, Receptors, Immunologic metabolism, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome genetics, Tumor Microenvironment genetics, Tumor-Associated Macrophages physiology, Monocytes metabolism, Pancreatic Neoplasms metabolism, Tumor-Associated Macrophages metabolism
- Abstract
Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa , C1qb , Trem2 , and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa , C1qb , and Trem2 , the other with high Chil3 , Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA , C1QB , and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients., (© 2021 Kemp et al.)
- Published
- 2021
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