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

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-11-01 Epub Date: 2024-10-16 DOI:10.1038/s44319-024-00288-2
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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酸性肿瘤微环境改变了巨噬细胞的昼夜节律。
肿瘤相关巨噬细胞(TAMs)具有促肿瘤生成的功能,因此是主要的治疗靶点,但巨噬细胞靶向疗法的疗效参差不齐,这凸显了我们对巨噬细胞如何在肿瘤微环境(TME)中受到调控的认识不全面。昼夜节律是巨噬细胞功能的关键调控因子,但巨噬细胞的昼夜节律如何受到肿瘤微环境的影响仍是未知数。在这里,我们展示了与肿瘤微环境相关的条件,如极化刺激、酸性 pH 值和乳酸盐能改变巨噬细胞的昼夜节律。据报道,环磷酸腺苷(cAMP)在巨噬细胞对酸性 pH 值的反应中发挥作用,但我们的研究结果表明,pH 值驱动的昼夜节律变化并非仅由 cAMP 信号介导。值得注意的是,时钟相关距离分析揭示了 TAMs 的昼夜节律紊乱。我们的数据表明,TAM 群体中昼夜节律的异质性可能是这种昼夜节律紊乱的原因。最后,我们报告了巨噬细胞的昼夜节律调节抑制了小鼠胰腺癌模型中的肿瘤生长。我们的工作展示了一种新的机制,即 TME 通过调节昼夜节律影响巨噬细胞的生物学特性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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