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的器官转移中发挥着关键作用。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（MAF）如何促进器官转移尚不清楚。在这里，我们的目的是破译MAF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独特作用。采用体内选择方法建立乳腺癌肺转移小鼠模型，该方法重复注射从MAF中纯化的转移细胞。小鼠肺。采用单细胞 RNA 测序 (scRNA-seq) 来研究 MAF 的异质性。使用转基因小鼠研究色氨酸2,3-双加氧酶阳性基质成纤维细胞（TDO2 MF）在肺转移中的贡献。我们在肺转移微环境中发现了3种MAF亚型，它们的转录组谱随着肺转移的演变而动态变化。作为主要亚型，MF仅由血小板源性生长因子受体α（PDGFRA）标记，主要位于转移边缘，T细胞在MF周围富集。值得注意的是，高 MF 特征与乳腺癌患者的较差生存率显着相关。在 MF 耗尽的实验性转移小鼠模型中，肺转移明显减少，T 细胞的抑制也显着减弱。我们发现TDO2 MF通过产生犬尿氨酸（KYN）来控制肺转移，KYN上调播散性肿瘤细胞（DTC）中铁蛋白重链1（FTH1）的水平，使DTC能够抵抗铁死亡。此外，TDO2 MF分泌的趋化因子C-C基序趋化因子配体8（CCL8）和C-C基序趋化因子配体11（CCL11）招募T细胞。 TDO2 MF 衍生的 KYN 诱导 T 细胞功能障碍。 MF 中 Tdo2 的条件性敲除可减少肺转移并增强免疫激活。我们的研究揭示了 TDO2 MF 在促进肺转移和转移微环境中 DTC 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有效治疗策略。© 2024 作者。约翰·威利出版的《癌症通讯》

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.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.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.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.© 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat‐sen University Cancer Center.