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Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain [RNAseq]

ABSTRACT: Breast cancer metastasis is the leading cause of breast cancer-related mortalities in women. Differential gene expression programs enriched in the primary tumor is able to distinguish patients that experience relapse to different organs. Epigenomic changes often underlie transcriptomic differences and give rise to stable phenotypes. However, the epigenomic differences present in organotropic metastasis remains underexplored. Here we profile the active chromatin landscape of the claudin-low cell line MDA-MB-231 and its metastatic subpopulations that preferentially grow in the brain (BrM2), and lung (LM2). We find that metastatic cells harbor increased promoter and enhancer activation. Using ATAC-seq, we also define transcription factors that are enriched in an organotropic manner. Chromatin accessibility of metastatic cells correlates with shorter progression-free survival and is enriched in patients who have more aggressive subtypes of breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138122 | GEO | 2020/02/01

REPOSITORIES: GEO

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Project description: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 three subtypes of MAFs in the lung metastatic microenvironment and their transcriptome profiles changed dynamically as lung metastasis evolves. As the predominant subtype, matrix fibroblasts (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 MFs 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 control pulmonary metastasis by producing kynurenine (KYN), which upregulated FTH1 level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MFs-secreted the chemokines CCL8 and 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.

Project description: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 three subtypes of MAFs in the lung metastatic microenvironment and their transcriptome profiles changed dynamically as lung metastasis evolves. As the predominant subtype, matrix fibroblasts (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 MFs 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 control pulmonary metastasis by producing kynurenine (KYN), which upregulated FTH1 level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2+ MFs-secreted chemokines CCL8 and 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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Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain [RNAseq]

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