Monocyte Regulation in Homeostasis and Malignancy

Monocytes are progenitors to macrophages and a subclass of dendritic cells (monocyte-derived dendritic cells, MoDCs), but they also act as circulating sensors that respond to environmental changes and disease. Technological advances have defined the production of classical monocytes in the bone marrow through the identification of lineage-determining transcription factors (LDTFs) and have proposed alternative routes of differentiation. Monocytes released into the circulation can be recruited to tissues by specific chemoattractants where they respond to sequential niche-specific signals that determine their differentiation into terminal effector cells. New aspects of monocyte biology in the circulation are being revealed, exemplified by the influence of cancer on the systemic alteration of monocyte subset abundance and transcriptional profiles. These changes can act to enhance the metastatic spread of primary cancers and may offer therapeutic opportunities. Mammalian monocyte development in the bone marrow from hematopoietic stem cells is driven by evolving and dynamic genomic enhancer landscapes and sequential binding of LDTFs.Monocyte fates are highly diverse; their plasticity and niche-specific regulation are beginning to be revealed in the contexts of homeostasis, inflammation, and cancer.Murine models of liver injury reveal that the interactions of monocytes with liver sinusoidal cells can lead to sequential alterations of genomic enhancer landscapes that ultimately drive Kupffer cell-specific expression of enhancers and genes.Murine models of genetic fate mapping, combined with studies of human cancers using single-cell transcriptome and proteome analysis, as well as bioinformatic-inferred algorithms for mapping trajectories of cellular differentiation, demonstrate that the tumor-associated macrophage phenotype is driven by tumor-specific features, regardless of their origin from monocytes or from yolk sac-derived tissue-resident monocytes.