CCL18 signaling from tumor-associated macrophages activates fibroblasts to adopt a chemoresistance-inducing phenotype.
CCL18 signaling from tumor-associated macrophages activates fibroblasts to adopt a chemoresistance-inducing phenotype.
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来自肿瘤相关巨噬细胞的 CCL18 信号激活成纤维细胞采取化学耐药性诱导表型
DOI：
10.1038/s41388-022-02540-2
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发表时间：
2023-01
期刊：
影响因子：
8
通讯作者：
Huang, Di
中科院分区：
文献类型：
--
作者：
Zeng, Wenfeng;Xiong, Lixiong;Wu, Wei;Li, Shunrong;Liu, Jiang;Yang, Linbing;Lao, Liyan;Huang, Penghan;Zhang, Mengmeng;Chen, Huiping;Miao, Nanyan;Lin, Zhirong;Liu, Zifei;Yang, Xinyu;Wang, Jiayi;Wang, Pei;Song, Erwei;Yao, Yandan;Nie, Yan;Chen, Jianing;Huang, Di
肿瘤相关成纤维细胞(CAF)的异质性可能归因于来源的差异。CD10和GPR77已被报道在乳腺癌中发现了一个诱导化疗耐药的CAF亚群。然而，CD10+GPR77+CAF形成的确切机制仍不清楚。在这项研究中，我们发现CCL18的表达与CD10+GPR77+CAF在乳腺癌中的密度呈正相关，并与化疗反应差有关。此外，肿瘤相关巨噬细胞(TAMs)分泌的CCL18在正常乳腺成纤维细胞(NBF)中激活CD10+GPR77+CAF表型，从而丰富肿瘤干细胞(CSCs)并诱导乳腺癌细胞产生化疗耐药。机制上，CCL18通过PITPNM3激活NF-κB信号，从而促进IL-6和IL-8的产生。此外，瘤内注射CCL18可显著诱导NBF的激活和异种移植瘤的化疗耐药。此外，通过抗CCL18抗体靶向CCL18可以抑制CD10+GPR77+CAF的形成，恢复体内的化疗敏感性，从而有效地控制肿瘤。总之，这些发现揭示了TAMs和成纤维细胞之间的炎症信号串扰是CD10+GPR77+CAF形成的原因，表明CCL18-PITPNM3信号是一个潜在的治疗靶点，可以阻断这一特定CAF亚型的激活和肿瘤的化疗耐药。
The heterogeneity of cancer-associated fibroblasts (CAFs) might be ascribed to differences in origin. CD10 and GPR77 have been reported to identify a chemoresistance-inducing CAF subset in breast cancer. However, the precise mechanism for the formation of the CD10+GPR77+ CAFs remains unknown. In this study, we found that CCL18 expression was positively correlated with the density of CD10+GPR77+ CAFs in breast cancer and associated with a poor response to chemotherapy. Moreover, CCL18 secreted by tumor-associated macrophages (TAMs) activated a CD10+GPR77+ CAF phenotype in normal breast-resident fibroblasts (NBFs), which could then enrich cancer stem cells (CSCs) and induce chemoresistance in breast cancer cells. Mechanistically, CCL18 activated NF-κB signaling via PITPNM3 and thus enhanced the production of IL-6 and IL-8. Furthermore, intratumoral CCL18 injection significantly induced the activation of NBFs and the chemoresistance of xenografts in vivo. In addition, targeting CCL18 by anti-CCL18 antibody could inhibit the formation of CD10+GPR77+ CAFs and recover the chemosensitivity in vivo, leading to effective tumor control. Collectively, these findings reveal that inflammatory signaling crosstalk between TAMs and fibroblasts is responsible for the formation of the CD10+GPR77+ CAFs, suggesting CCL18–PITPNM3 signaling is a potential therapeutic target to block the activation of this specific CAF subtype and tumor chemoresistance.
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DOI：
10.1084/jem.20130240
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Islam SA;Ling MF;Leung J;Shreffler WG;Luster AD
通讯作者：
Luster AD
影响因子：
64.8
作者：
Kuppe C;Ibrahim MM;Kranz J;Zhang X;Ziegler S;Perales-Patón J;Jansen J;Reimer KC;Smith JR;Dobie R;Wilson-Kanamori JR;Halder M;Xu Y;Kabgani N;Kaesler N;Klaus M;Gernhold L;Puelles VG;Huber TB;Boor P;Menzel S;Hoogenboezem RM;Bindels EMJ;Steffens J;Floege J;Schneider RK;Saez-Rodriguez J;Henderson NC;Kramann R
通讯作者：
Kramann R
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
28.2
作者：
Kieffer, Yann;Hocine, Hocine R.;Mechta-Grigoriou, Fatima
通讯作者：
Mechta-Grigoriou, Fatima
影响因子：
8
作者：
Comito, G.;Giannoni, E.;Chiarugi, P.
通讯作者：
Chiarugi, P.