Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis

IF 5.6 2区化学 Q1 CHEMISTRY, MEDICINAL

Journal of Chemical Information and Modeling Pub Date : 2024-09-05 DOI:10.1126/science.adn0327

Matthew D. Park, Jessica Le Berichel, Pauline Hamon, C. Matthias Wilk, Meriem Belabed, Nader Yatim, Alexis Saffon, Jesse Boumelha, Chiara Falcomatà, Alexander Tepper, Samarth Hegde, Raphaël Mattiuz, Brian Y. Soong, Nelson M. LaMarche, Frederika Rentzeperis, Leanna Troncoso, Laszlo Halasz, Clotilde Hennequin, Theodore Chin, Earnest P. Chen, Amanda M. Reid, Matthew Su, Ashley Reid Cahn, Laura L. Koekkoek, Nicholas Venturini, Shira Wood-isenberg, Darwin D’souza, Rachel Chen, Travis Dawson, Kai Nie, Zhihong Chen, Seunghee Kim-Schulze, Maria Casanova-Acebes, Filip K. Swirski, Julian Downward, Nicolas Vabret, Brian D. Brown, Thomas U. Marron, Miriam Merad

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Abstract

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor–like cells in lung tumors. These cells are a major source of interleukin (IL)–1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺–expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

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造血衰老通过助长IL-1⍺驱动的紧急骨髓造血来促进癌症。

年龄是癌症的主要风险因素，但衰老如何影响肿瘤控制仍不清楚。在这里，我们证实，免疫系统的衰老（与基质和肿瘤的年龄无关）会推动肺癌的进展。造血衰老会增强紧急骨髓造血，导致髓样祖细胞在肺肿瘤局部聚集。这些细胞是IL-1⍺的主要来源，而IL-1⍺可驱动增强的髓系反应。与年龄相关的DNMT3A衰退会增强IL-1⍺的产生，在肿瘤发生的早期破坏IL-1R1信号可使骨髓造血正常化，并减缓肺、结肠和胰腺肿瘤的生长。在人类肿瘤中，我们发现表达IL-1⍺的单核细胞衍生巨噬细胞的富集与年龄、较差的存活率和复发有关，这揭示了衰老如何促进癌症的发生，并提供了可行的治疗策略。

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来源期刊

Journal of Chemical Information and Modeling 化学-化学综合

CiteScore

9.80

自引率

10.70%

发文量

529

审稿时长

1.4 months

期刊介绍： The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery. Astute chemists, computer scientists, and information specialists look to this monthly’s insightful research studies, programming innovations, and software reviews to keep current with advances in this integral, multidisciplinary field. As a subscriber you’ll stay abreast of database search systems, use of graph theory in chemical problems, substructure search systems, pattern recognition and clustering, analysis of chemical and physical data, molecular modeling, graphics and natural language interfaces, bibliometric and citation analysis, and synthesis design and reactions databases.