Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.

ABSTRACT

Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.