Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 16, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2119168119
Keywords
macrophage; collagen; fibrosis; stellate cell; pancreatic cancer
Categories
Funding
- Cancer Center Support Grant at the Laura and Isaac Perlmutter Cancer Center [P30CA016087]
- NIH/National Cancer Institute Grants [CA210263, P01CA117969, CA232124]
- Lustgarten Foundation
- SU2C
- [S10 OD021747]
- [T32GM066704]
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Tumor-associated macrophages play a role in remodeling the extracellular matrix, which affects the growth and development of tumors.
A hallmark of pancreatic tumors is their highly desmoplastic stroma composed of fibroblasts, immune cells, and a dense network of collagen fibers. Tumor-associated macrophages are one of the most abundant immune cell populations in the pancreatic tumor stroma. Their protumorigenic function has been attributed predominantly to their capacity to promote immune evasion and metastasis. Tumor-associated macrophages are also well known for their role in the remodeling of the stroma via collagen production and degradation, with the latter being mediated by mannose receptor (MRC1)-dependent endocytosis of collagen. Here we show that MRC1-mediated collagen internalization and subsequent lysosomal degradation by macrophages harboring a tumor-associated phenotype are accompanied by the accumulation of collagen-derived intracellular free amino acids and increased arginine biosynthesis. The resulting increase in intracellular arginine levels leads to the up-regulation of inducible nitric oxide synthase and the production of reactive nitrogen species. Furthermore, reactive nitrogen species derived from internalized and degraded collagen promotes a profibrotic phenotype in pancreatic stellate cells resulting in enhanced intratumoral collagen deposition. Overall, our findings identify a role for extracellular matrix remodeling in the functional modulation of tumor-associated macrophages via metabolic rewiring.
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