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Updated: Jun 10, 2025
Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
Circadian rhythms of macrophages are altered by the acidic tumor microenvironment
Amelia M Knudsen-Clark1, Daniel Mwangi2, Juliana Cazarin2
1Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.
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.
Insights
Tumor microenvironment conditions disrupt macrophage circadian rhythms, impacting cancer progression. Restoring these rhythms in macrophages suppresses pancreatic tumor growth.
Area of Science:
- Immunology
- Cancer Biology
- Chronobiology
Background:
- Tumor-associated macrophages (TAMs) promote tumor growth, making them therapeutic targets.
- Macrophage function is regulated by the circadian clock, but TME influence is unknown.
- Current macrophage-targeting therapies show variable efficacy, suggesting incomplete understanding of TAM regulation.
Purpose of the Study:
- To investigate how the tumor microenvironment (TME) influences macrophage circadian rhythms.
- To determine if circadian disruption in TAMs contributes to tumor progression.
- To explore the therapeutic potential of targeting macrophage circadian rhythms in cancer.
Main Methods:
- Analysis of macrophage circadian rhythms under TME-mimicking conditions (e.g., acidic pH, lactate).
- Investigation of signaling pathways, including cyclic AMP (cAMP), involved in pH-mediated circadian changes.
- Application of clock correlation distance analysis to assess TAM circadian rhythmicity.
- Evaluation of circadian regulation of macrophages in a murine model of pancreatic cancer.
Main Results:
- TME-associated factors like polarizing stimuli, acidic pH, and lactate alter macrophage circadian rhythms.
- pH-driven circadian rhythm alterations are not solely mediated by cAMP signaling.
- Circadian disorder was observed in TAMs, potentially due to heterogeneity within the TAM population.
- Circadian regulation of macrophages was found to suppress tumor growth in a pancreatic cancer model.
Conclusions:
- The TME actively modulates macrophage circadian rhythms through various conditions.
- Disrupted circadian rhythms in TAMs represent a novel mechanism of TME influence on macrophage biology.
- Targeting macrophage circadian rhythms offers a potential new strategy for cancer therapy.
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