色氨酸-2,3-二氧合酶阳性基质成纤维细胞通过犬尿氨酸介导的转移细胞铁蛋白沉积抗性和 T 细胞功能障碍助长乳腺癌肺转移。

IF 20.1 1区 医学 Q1 ONCOLOGY Cancer Communications Pub Date : 2024-09-02 DOI:10.1002/cac2.12608
Yongcan Liu, Shanchun Chen, Xueying Wan, Rui Wang, Haojun Luo, Chao Chang, Peijin Dai, Yubi Gan, Yuetong Guo, Yixuan Hou, Yan Sun, Yong Teng, Xiaojiang Cui, Manran Liu
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引用次数: 0

摘要

背景:肿瘤转移是癌症患者生存的主要威胁:肿瘤转移是癌症患者生存的主要威胁。器官特异性生态位在肿瘤器官转移中起着关键作用。成纤维细胞是转移微环境的重要组成部分,但异质性转移相关成纤维细胞(MAFs)是如何促进器官转移的还不清楚。在此,我们旨在破译MAFs的异质性,并阐明这些成纤维细胞在乳腺癌肺转移形成中的不同作用:方法:通过反复注射从小鼠肺部纯化的转移细胞的体内选择方法,建立了乳腺癌肺转移小鼠模型。采用单细胞 RNA 测序(scRNA-seq)研究 MAFs 的异质性。利用转基因小鼠研究色氨酸-2,3-二氧合酶阳性基质成纤维细胞(TDO2+ MFs)在肺转移中的贡献:结果:我们在肺转移微环境中发现了三种亚型的基质成纤维细胞,它们的转录组特征随着肺转移的发展而发生动态变化。作为最主要的亚型,MFs完全以血小板衍生生长因子受体α(PDGFRA)为标志,主要位于转移灶边缘,T细胞富集在MFs周围。值得注意的是,高MF特征与乳腺癌患者的低生存率密切相关。在MF缺失的实验性转移小鼠模型中,肺转移明显减少,T细胞的抑制作用也显著减弱。我们发现,TDO2+中频因子通过产生犬尿氨酸(KYN)控制肺转移,而犬尿氨酸能上调播散性肿瘤细胞(DTCs)中铁蛋白重链1(FTH1)的水平,使DTCs能抵抗铁蛋白沉积。此外,TDO2+ MF分泌的趋化因子C-C基团趋化因子配体8(CCL8)和C-C基团趋化因子配体11(CCL11)可招募T细胞。TDO2+ MF衍生的KYN诱导T细胞功能障碍。有条件地敲除MF中的Tdo2可减少肺转移并增强免疫激活:我们的研究揭示了TDO2+ MFs在促进肺转移和DTCs在转移龛中的免疫逃避中的关键作用。结论:我们的研究揭示了 TDO2+ MFs 在促进肺转移和 DTCs 在转移龛中免疫逃避中的关键作用,这表明针对肺特异性基质细胞的代谢可能是乳腺癌肺转移患者的一种有效治疗策略。
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Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.

Background: Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.

Methods: Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2+ MFs) in lung metastasis.

Results: We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2+ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2+ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.

Conclusions: Our study reveals crucial roles of TDO2+ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.

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来源期刊
Cancer Communications
Cancer Communications Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
25.50
自引率
4.30%
发文量
153
审稿时长
4 weeks
期刊介绍: Cancer Communications is an open access, peer-reviewed online journal that encompasses basic, clinical, and translational cancer research. The journal welcomes submissions concerning clinical trials, epidemiology, molecular and cellular biology, and genetics.
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