Dataset Information

Comparing breast tumor cell-induced gene expression in primary mammary fibroblasts from MEKK1-deficient mice to fibroblasts from MEKK1+/+ mice

ABSTRACT: This study examined the importance of intracellular kinase MEKK1 in breast tumor-induced on gene expression in non-tumor mammary cells. The hypothesis tested in this study was that the kinase MEKK1 regulates breast tumor cells-induced expression of fibroblast genes that change the tumor microenvironment to promote breast tumor progression to metastasis. Results reveal that MEKK1 regulates expression of chemokines and other genes in normal breast stroma cells that contribute to the development of a tumor microenvironment that promotes metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE167130 | GEO | 2021/02/20

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Comparing breast tumor cell-induced gene expression in primary mammary fibroblasts from MEKK1-deficient mice to fibroblasts from MEKK1+/+ mice

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets