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Single-cell RNA sequencing reveals cellular and molecular heterogeneity and distinct immunosuppressive traits in the MMTV-R26Met syngeneic TNBC model

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer with limited targeted therapies. To model TNBC heterogeneity in an immunocompetent setting, we established syngeneic grafts derived from the TNBC MMTV-R26Met genetically engineered mouse model, which preserve both the molecular identity and immune landscape of primary tumors. These grafts recapitulate features of distinct TNBC subtypes, providing a physiologically relevant preclinical platform to investigate tumor–immune interactions and therapy response. Here, we performed single-cell RNA sequencing (scRNA-seq) on four syngeneic tumors (S34, S35, S37, and S39), generating transcriptomic profiles from 22,046 cells. Clustering identified cell populations spanning malignant epithelial, stromal, endothelial, and diverse immune subsets. Tumors displayed subtype-specific traits, including oxidative phosphorylation programs with N2-like neutrophils and epithelial–mesenchymal transition with M2-like macrophages. Despite overall low T cell infiltration, inhibitory receptors and myeloid checkpoint ligands were broadly expressed, highlighting strongly immunosuppressive microenvironments. These datasets provide a resource for dissecting TNBC subtype heterogeneity in an immunocompetent context and offer a preclinical framework to explore mechanisms of immune evasion and therapeutic response.

ORGANISM(S): Mus musculus

PROVIDER: GSE306716 | GEO | 2026/02/22

REPOSITORIES: GEO

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Project description:The goal of this dataset is to compare the gene expression patterns between primary and metastatic tumors Metastatic cancer patients typically have short survival times and their successful treatment represents one of most challenging aspects of patient care. This poor prognostic behavior is likely due to many factors, including increased clonal heterogeneity, multiple drug resistance mechanisms, and the role of the tumor microenvironment. The AURORA US Metastasis Project was established to collect and molecularly characterize specimens from 55 breast cancer (BC) patients representing 51 primary cancers and 102 metastases. The 153 unique tumors were assayed using RNAseq, tumor/germline DNA exomes and low pass whole genome sequencing, and global DNA methylation microarrays. We found intrinsic molecular subtype differences between primary tumors and their matched metastases to be rare in triple negative breast cancer (TNBC)/Basal-like subtype tumors. Conversely, tumor subtype changes were relatively frequent in estrogen receptor positive (ER+) cancers where ~30% of Luminal A cases switched to Luminal B or HER2-enriched (HER2E) subtype. Clonal evolution studies identified changes in expression subtype coincident with DNA clonality shifts, especially involving HER2 amplification and/or the HER2E expression subtype. Microenvironment differences varied according to tumor subtype where ER+/Luminal metastases had lower fibroblast and endothelial cell content, while TNBC/Basal-like metastases showed a dramatic decrease in adaptive immunity. In 17% of metastatic tumors, we identified DNA methylation and/or focal DNA deletions near HLA-A that were associated with its significantly reduced expression, and with lower immune cell infiltrates. We also identified low immune cell features in brain and liver metastases when compared to other metastatic sites, even within the same patient. These findings have direct implications for the treatment of metastatic breast cancer patients with immune- and HER2-targeting therapies and suggest potential novel therapeutic avenues for the improvement of outcomes for some MBC patients.

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Single-cell RNA sequencing reveals cellular and molecular heterogeneity and distinct immunosuppressive traits in the MMTV-R26Met syngeneic TNBC model

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