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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

ABSTRACT: Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

PROVIDER: PRJNA949598 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23979317.fastq.gz	Fastqsanger.gz
	SRR23979318.fastq.gz	Fastqsanger.gz
	SRR23979319.fastq.gz	Fastqsanger.gz
	SRR23979320.fastq.gz	Fastqsanger.gz
	SRR23979321.fastq.gz	Fastqsanger.gz

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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

Project description:We investigate non-genomic mechanisms determining cellular response to EGFR inhibitors in triple negative breast cancer (TNBC). We integrate methods for cellular barcoding and single-cell transcriptomics to enable cell lineage tracing and explore the subclonal evolution of adaptation in an established preclinical model of TNBC in response to incremental concentrations of Afatinib, a second generation EGFR-TKI that irreversibly inhibits both EGFR and HER2. Retrospective lineage tracing data analysis uncovered a pre-existing subpopulation of rare Afatinib-tolerant cells displaying distinct biological features, such as elevated mRNA levels of the IGFBP2 gene. Furthermore, we investigated temporal coordination of transcriptional programs in drug resistant clones with high replication fitness by reordering cells along a pseudotime trajectory. Interestingly, it revealed the activation of biological processes, such as fatty acid metabolism, which have previously been linked to EGFR-TKIs resistance mechanisms.

2024-03-25 | GSE228154 | GEO

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

Project description:Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

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Lineage Tracing Reveals Clone-Specific Responses to Doxorubicin in Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer, characterized by aggressive growth and high intratumor heterogeneity, presents a significant clinical challenge. Here, we use a lineage-tracing system, ClonMapper, which couples heritable clonal identifying tags with single-cell RNA-sequencing (scRNA-seq), to better elucidate the response to doxorubicin in a model of TNBC. We demonstrate that, while there is a dose-dependent reduction in overall clonal diversity, there is no pre-existing resistance signature among surviving clones. Separately, we found the existence of two transcriptomically distinct clonal subpopulations that remain through the course of treatment. Among clones persisting across multiple samples we identified divergent phenotypes, suggesting a response to treatment independent of clonal identity. Finally, a subset of clones harbor novel changes in expression following treatment. The clone and sample specific responses to treatment identified herein highlight the need for better personalized treatment strategies to overcome tumor heterogeneity.

2025-03-18 | GSE291679 | GEO

Lineage Tracing Reveals Clone-Specific Responses to Doxorubicin in Triple-Negative Breast Cancer [scRNA-seq]

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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

Project description:BackgroundMost primary Triple Negative Breast Cancers (TNBCs) show amplification of the Epidermal Growth Factor Receptor (EGFR) gene, leading to increased protein expression. However, unlike other EGFR-driven cancers, targeting this receptor in TNBC yields inconsistent therapeutic responses.MethodsTo elucidate the underlying mechanisms of this variability, we employ cellular barcoding and single-cell transcriptomics to reconstruct the subclonal dynamics of EGFR-amplified TNBC cells in response to afatinib, a tyrosine kinase inhibitor (TKI) that irreversibly inhibits EGFR.ResultsIntegrated lineage tracing analysis revealed a rare pre-existing subpopulation of cells with distinct biological signature, including elevated expression levels of Insulin-Like Growth Factor Binding Protein 2 (IGFBP2). We show that IGFBP2 overexpression is sufficient to render TNBC cells tolerant to afatinib treatment by activating the compensatory insulin-like growth factor I receptor (IGF1-R) signalling pathway. Finally, based on reconstructed mechanisms of resistance, we employ deep learning techniques to predict the afatinib sensitivity of TNBC cells.ConclusionsOur strategy proved effective in reconstructing the complex signalling network driving EGFR-targeted therapy resistance, offering new insights for the development of individualized treatment strategies in TNBC.

| S-EPMC11008053 | biostudies-literature

Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells

Project description:Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-Seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-Seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ propDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs, and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s

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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-25 | GSE228382 | GEO

cIAP1 regulates the EGFR/Snai2 axis in triple negative breast cancer cells

Project description:Inhibitor of apoptosis (IAP) proteins constitute a conserved family of molecules which regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer MDA-MB231 cell line were treated with SM83, a pan-IAP inhibitor developed by us, and tumor nodules were profiled for gene expression. Our work suggests that IAP-targeted therapy could contribute to EGFR inhibition and the reduction of its downstream mediators. This approach could be particularly effective in cells characterized by high levels of EGFR and Snai2, such as triple negative breast cancer.

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Clonal lineage tracing of innate immune cells in human cancer

Project description:Clonal lineage tracing of innate immune cells in human cancer

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Lineage Tracing Reveals Clone-Specific Responses to Doxorubicin in Triple-Negative Breast Cancer

Project description:Lineage Tracing Reveals Clone-Specific Responses to Doxorubicin in Triple-Negative Breast Cancer

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