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Spatiotemporal organisation of residual disease in mouse and human BRCA1-deficient mammary tumors and breast cancer

ABSTRACT: Breast cancer remains one of the prominent causes of death worldwide. Although chemotherapeutic agents often result in substantial reduction of primary or metastatic tumors, remaining drug-tolerant tumor cell populations, known as minimal residual disease (MRD), pose a significant risk of recurrence and therapy resistance. In this study, we describe the spatiotemporal organisation of therapy response and MRD in BRCA1;p53-deficient mouse mammary tumors and human clinical samples using a multimodal approach. By integrating single-cell RNA sequencing, spatial transcriptomics, and imaging mass cytometry across multiple treatment timepoints, we characterise dynamic interactions between tumor cell subpopulations and their surrounding microenvironment. Our analysis identifies a distinct, drug-tolerant epithelial-mesenchymal transition (EMT) cancer cell population, which exhibits a conserved expression program in human BRCA1-deficient tumors and significantly correlates with adverse clinical outcomes. We further reveal the spatial distribution of residual EMT-like tumor cells within specific anatomical niches, providing a framework for understanding the persistence of MRD and potential therapeutic vulnerabilities. These findings yield a comprehensive molecular roadmap of MRD, opening new avenues for therapeutic strategies targeting EMT-driven drug tolerance and tumor relapse.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE299631 | GEO | 2025/06/19

REPOSITORIES: GEO

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Project description:Despite the clinical success of targeted therapy inhibitors, tumor responses are transient, and a subpopulation of residual drug-tolerant cells may seed resistance. Understanding minimal residual disease (MRD) mechanisms and the connection with dormancy-like traits may guide strategies to target drug-tolerant persister cells and optimize target therapies. Here, we studied the relationship between persister cell tolerance to BRAF and MEK inhibitors (BRAFi + MEKi) and expression of nuclear receptor subfamily 2 group F member 1 (NR2F1), which has been linked to tumor dormancy in the context of cutaneous melanoma. In previously published RNA-seq datasets, NR2F1 expression was enriched in melanoma samples following BRAF inhibitor and MEK inhibitor (BRAFi + MEKi) treatment compared to pre-treatment patient-matched samples. We also found that NR2F1 is highly expressed in the residual drug-tolerant cell state following BRAFi + MEKi treatment in patient-derived and cell line-derived melanoma xenografts. Additionally, xenografts overexpressing NR2F1 displayed higher tumor growth and poorer animal survival following BRAFi + MEKi treatment compared to control xenografts expressing basal levels of NR2F1. In vitro, NR2F1-overexpressing cells showed increased tumor proliferation and higher expression of cell cycle and survival-related proteins on targeted therapy, such as phosphorylation of both RB and S6K proteins. In addition, NR2F1, highly expressed in invasive melanoma cells, was sufficient to promote invasiveness following BRAFi + MEKi in 3D tumor spheroid assays. Furthermore, when compared to young mice, NR2F1 was overexpressed in tumor xenografts in an old microenvironment. The use of shRNA NR2F1 in older mice led to slower tumor growth and the highest survival in animals on BRAFi + MEKi treatment. We also tested a pharmacological approach to target drug-tolerant persister cells that overexpress NR2F1 on BRAFi + MEKi treatment. The inhibition of mTORC1 delayed NR2F1-overexpressing cell proliferation compared to non-NR2F1-overexpressing cells on targeted therapy. Altogether, our findings suggest that NR2F1 plays a role in the persistence of MRD in melanoma, indicating that targeting NR2F1 expression could improve targeted therapy outcomes in melanoma patients.

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Spatiotemporal organisation of residual disease in mouse and human BRCA1-deficient mammary tumors and breast cancer

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