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癌细胞衍生的S100A11促进雌激素受体阳性乳腺癌中的巨噬细胞募集。

Cancer-cell derived S100A11 promotes macrophage recruitment in ER+ breast cancer.

作者信息

Lee Sanghoon, Cho Youngbin, Li Yiting, Li Ruxuan, Brown Daniel, McAuliffe Priscilla, Lee Adrian V, Oesterreich Steffi, Zervantonakis Ioannis K, Osmanbeyoglu Hatice Ulku

机构信息

Department of Biomedical Informatics, School of Medicine, University of Pittsburgh, Pittsburgh, 15206, U.S.A.

UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, 15213 U.S.A.

出版信息

bioRxiv. 2024 Mar 26:2024.03.21.586041. doi: 10.1101/2024.03.21.586041.

Abstract

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA-sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in 3D models, we showed that S100A11 expression levels in ER+ cancer cells predict macrophage infiltration patterns. Neutralizing S100A11 decreased macrophage recruitment, both in cancer cell lines and in a clinically relevant patient-derived organoid model, underscoring its role as a paracrine regulator of cancer-macrophage interactions in the protumorigenic TME. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.

摘要

巨噬细胞在推动乳腺肿瘤的发生、发展及治疗抵抗中起关键作用,尤其是在雌激素受体阳性(ER+)肿瘤中,它们浸润受癌细胞分泌因子影响的肿瘤微环境(TME)。通过分析来自25个ER+肿瘤的单细胞RNA测序数据,我们阐明了癌细胞与巨噬细胞之间的相互作用,将巨噬细胞密度与上皮癌细胞密度相关联。我们发现S100A11,一种先前未被探索的巨噬细胞-癌症相互作用因子,可预测ER+肿瘤中高巨噬细胞密度和不良预后。我们发现重组S100A11以剂量依赖的方式增强巨噬细胞浸润和迁移。此外,在三维模型中,我们表明ER+癌细胞中的S100A11表达水平可预测巨噬细胞浸润模式。在癌细胞系和临床相关的患者来源类器官模型中,中和S100A11均可减少巨噬细胞募集,强调了其作为促肿瘤TME中癌症-巨噬细胞相互作用的旁分泌调节因子的作用。本研究为ER+乳腺肿瘤中巨噬细胞与癌细胞之间相互作用提供了新见解,突出了S100A11作为调节富含巨噬细胞的肿瘤微环境的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d63/10996512/1a59df400053/nihpp-2024.03.21.586041v1-f0001.jpg

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