Ontology highlight
ABSTRACT:
PROVIDER: PRJNA700464 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13857300_1.fastq.gz | Fastqsanger.gz | |||
| SRR13857300_2.fastq.gz | Fastqsanger.gz | |||
| SRR13857301_1.fastq.gz | Fastqsanger.gz | |||
| SRR13857301_2.fastq.gz | Fastqsanger.gz | |||
| SRR13857302_1.fastq.gz | Fastqsanger.gz |
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Project description:Several single-cell studies have reported transcriptomic, genomic and epigenomic dysregulation in breast cancer tissue. However, the peripheral immune landscape of breast cancer patients remains poorly understood. We report the analysis of the single-cell transcriptomes of more than 110,000 peripheral blood mononuclear cells (PBMCs) of healthy and metastatic breast cancer patients. Integrated analysis revealed depleted memory B cells (BMEM) and T cell subpopulations, including transitional CD8 T, CD4 naïve, CD4 ribosome and MAIT cells in the circulating immune landscape of metastatic breast cancer patients. Nevertheless, metastatic breast cancer patients showed marked enrichment of pro-inflammatory NKG7 high monocytes, M1 macrophages, migratory myeloid, T memory stem cells (TSCM), CD4 T effector memory (TEM) and CD4 T central memory (TCM) cells. Further, interrogation of single-cell transcriptomes based on metastatic disease state, i.e. stable vs progressive, revealed distinct compositional and transcriptional changes in PBMCs correlated with the metastatic burden. The antigen inexperienced CD4 naïve T cells and cytotoxic MAIT cells are further depleted in the progressive metastatic stage. Surprisingly, the pro-inflammatory classical monocytes and CD4 T effector memory (TEM) cells are also depleted in the progressive metastatic state, indicating their potential role in stable metastatic disease. Lastly, the receptor-ligand relationships, such as cell-cell contact, ECM-receptor interactions, and cytokine transcription profiles, were tightly associated with metastatic burden. Collectively, our study provides unique molecular insight into the peripheral immune system operating in metastatic breast cancers and identified novel surrogate biomarkers of metastatic disease.
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Project description:Metastatic breast cancer remains largely incurable, and the mechanisms driving the transition from primary to metastatic breast cancer remain elusive. We analyzed the complex landscape of estrogen receptor (ER)-positive breast cancer primary and metastatic tumors using scRNA-seq data from twenty-three female patients with either primary or metastatic disease. By employing single-cell transcriptional profiling of unpaired patient samples, we sought to elucidate the genetic and molecular mechanisms underlying changes in the metastatic tumor ecosystem. We identified specific subtypes of stromal and immune cells critical to forming a pro-tumor microenvironment in metastatic lesions, including CCL2+ macrophages, exhausted cytotoxic T cells, and FOXP3+ regulatory T cells. Analysis of cell-cell communication highlights a marked decrease in tumor-immune cell interactions in metastatic tissues, likely contributing to an immunosuppressive microenvironment. In contrast, primary breast cancer samples displayed increased activation of the TNF-α signaling pathway via NF-kB, indicating a potential therapeutic target. Our study comprehensively characterizes the transcriptional landscape encompassing primary and metastatic breast cancer.
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Project description:Metastatic breast cancer is the leading cause of death amongst patients that develop breast cancer. The molecular drivers of metastatic breast cancer are largely unknown. Treatment of metastatic breast cancer is limited to systemic cytotoxic chemotherapies, which often deteriorate patient quality of life, and tumors often become refractory, resulting in incurable disease. The most frequently mutated gene associated with metastatic breast cancer is TP53. The TP53R248W hotspot missense mutation is associated with poor prognosis in breast cancer. To understand the intrinsic transcriptomic and genomic landscape of metastatic breast cancer driven by mutant p53, we generated a somatic mouse model driven by mammary epithelial specific expression of Trp53R248W. Primary tumors were highly metastatic and reflected the human molecular subtypes of luminal A, luminal B, HER2, and TNBC, with TNBC comprising the majority (79%) of these tumors. Transcriptomic profiling revealed primary tumor heterogeneity characterized by three intrinsic subtypes (1) stem-cell like; (2) well-differentiated metabolic like; and (3) immune suppressed. Stem-cell like tumors activate ribosome biosynthesis and E2F signaling. These tumors harbor amplifications in Met, Birc3, Yap1 and deletions in Nf1, Pik3r1, and Rad17. Well-differentiated metabolic like mammary tumors activate cytochrome P450 enzymes, estrogen signaling and branched chain amino acid degradation and harbor mutations in the Pten pathway. Immune suppressed tumors enrich for processes related to immune suppression. These tumors have high mutation burden, frequently mutate Traf7 and delete Cdkn2a. This is the most comprehensive transcriptomic and genomic profiling of mutant p53 driven breast tumors and sheds light on their heterogenous nature and distinct intrinsic programs that may inform targeted therapy for metastatic breast cancer.
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