Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Amelia M Knudsen-Clark; Daniel Mwangi; Juliana Cazarin; Kristina Morris; Cameron Baker; Lauren M Hablitz; Matthew N McCall; Minsoo Kim; Brian J Altman

doi:10.1038/s44319-024-00288-2

PubMed · 39415049

Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.

Amelia M Knudsen-Clark·Daniel Mwangi·Juliana Cazarin·Kristina Morris·Cameron Baker·Lauren M Hablitz·Matthew N McCall·Minsoo Kim·Brian J Altman

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Abstract

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms.

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Tumor Microenvironment Circadian Rhythm Animals Mice Hydrogen-Ion Concentration Macrophages Tumor-Associated Macrophages Humans Cyclic AMP Pancreatic Neoplasms Signal Transduction Circadian Clocks Mice, Inbred C57BL Cell Line, Tumor Circadian Rhythms Immuno-oncology Immunology Macrophage Journal Article

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Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Kristina Morris, Cameron Baker, Lauren M Hablitz, Matthew N McCall, Minsoo Kim, Brian J Altman. 2024-10-16. Circadian rhythms of macrophages are altered by the acidic tumor microenvironment.. https://doi.org/10.1038/s44319-024-00288-2

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