| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Cancer Communications, Vol 44, Iss 11, Pp 1261-1286 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2523-3548 |
| DOI: |
10.1002/cac2.12608 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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