1. Multiomic characterization of pancreatic cancer-associated macrophage polarization reveals deregulated metabolic programs driven by the GM-CSF–PI3K pathway
- Author
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Boyer, Seth, Lee, Ho-Joon, Steele, Nina, Zhang, Li, Sajjakulnukit, Peter, Andren, Anthony, Ward, Matthew H, Singh, Rima, Basrur, Venkatesha, Zhang, Yaqing, Nesvizhskii, Alexey I, di Magliano, Marina Pasca, Halbrook, Christopher J, and Lyssiotis, Costas A
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Immunology ,Medical Biochemistry and Metabolomics ,Oncology and Carcinogenesis ,Immunotherapy ,Digestive Diseases ,Cancer ,Pancreatic Cancer ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Animals ,Cell Line ,Tumor ,Cell Transformation ,Neoplastic ,Gene Expression Profiling ,Granulocyte-Macrophage Colony-Stimulating Factor ,Humans ,Metabolic Networks and Pathways ,Metabolomics ,Mice ,Mice ,Inbred C57BL ,Pancreatic Neoplasms ,Proteomics ,Signal Transduction ,Transcription Factors ,Tumor-Associated Macrophages ,pancreatic cancer ,tumor-associated macrophages ,metabolomics ,proteomics ,Human ,Mouse ,cancer biology ,human ,immunology ,inflammation ,mouse ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The pancreatic ductal adenocarcinoma microenvironment is composed of a variety of cell types and marked by extensive fibrosis and inflammation. Tumor-associated macrophages (TAMs) are abundant, and they are important mediators of disease progression and invasion. TAMs are polarized in situ to a tumor promoting and immunosuppressive phenotype via cytokine signaling and metabolic crosstalk from malignant epithelial cells and other components of the tumor microenvironment. However, the specific distinguishing features and functions of TAMs remain poorly defined. Here, we generated tumor-educated macrophages (TEMs) in vitro and performed detailed, multiomic characterization (i.e., transcriptomics, proteomics, metabolomics). Our results reveal unique genetic and metabolic signatures of TEMs, the veracity of which were queried against our in-house single-cell RNA sequencing dataset of human pancreatic tumors. This analysis identified expression of novel, metabolic TEM markers in human pancreatic TAMs, including ARG1, ACLY, and TXNIP. We then utilized our TEM model system to study the role of mutant Kras signaling in cancer cells on TEM polarization. This revealed an important role for granulocyte-macrophage colony-stimulating factor (GM-CSF) and lactate on TEM polarization, molecules released from cancer cells in a mutant Kras-dependent manner. Lastly, we demonstrate that GM-CSF dysregulates TEM gene expression and metabolism through PI3K-AKT pathway signaling. Collectively, our results define new markers and programs to classify pancreatic TAMs, how these are engaged by cancer cells, and the precise signaling pathways mediating polarization.
- Published
- 2022