Expression profile of castration-resistant LY6D+ luminal progenitors during prostate tumourigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA729674 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14521500.fastq.gz | Fastqsanger.gz | |||
| SRR14521501.fastq.gz | Fastqsanger.gz | |||
| SRR14521502.fastq.gz | Fastqsanger.gz | |||
| SRR14521503.fastq.gz | Fastqsanger.gz | |||
| SRR14521504.fastq.gz | Fastqsanger.gz |
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Project description:By using luminal lineage tracing model, here we report the regulatory network underlying intrinsically castration-resistant LY6D+ luminal progenitors during prostate tumourigenesis. The luminal cell-specific PTEN deficient mouse model of PCa (K8-CreERT2;PtenFlox/Flox;R26-StopFlox/Flox-EYFP (K8PY) and the control K8-CreERT2;R26-StopFlox/Flox-EYFP (K8Y) mice) are used in this study.
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Project description:In the normal prostate, most basal and some luminal cells are castration-resistant (CR). The identity of these CR cells and their relation to CR prostate cancer are unresolved. We compared single-cell expression profiles of prostate cells sorted from hormonally naïve (HN) and castrated mice. We found both basal and luminal-localized cells, particularly the latter, were molecularly heterogeneous. CR luminal cells and a subset of HN luminal cells exhibited a similar “intermediate” expression pattern, including high-level expression of multiple prostate stem/progenitor marker genes and androgen receptor gene. We validated LY6D as a marker linking CR luminal cells to luminal progenitors. LY6D+ prostate cells, including LY6D+ luminal cells, were enriched for organoid-forming potential regardless of the presence or absence of androgen. Krt8-based lineage-tracing revealed that LY6D+ CR luminal cells produced LY6D- normal luminal cells upon regeneration, but LY6D+ luminal cancer cells under PTEN-deficiency. Furthermore, prostate cancers originating from CR luminal cells (LY6D+) exhibited a more advanced phenotype than those from HN luminal cells (LY6D+ or LY6D-). Lastly, LY6D amplification/upregulation appear associated with advanced prostate cancer in patient samples. Together, our studies demonstrate LY6D as a novel progenitor marker predictive of lethal CR disease.
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Project description:Identification of defined cell populations with stem/progenitor properties is key for our understanding of prostate development and tumorigenesis. Prior studies have provided strong evidence of the existence of prostate luminal progenitors, but their identity and functional properties remains unknown. Using an unbiased novel bigenic mouse model to specifically earmark, prospectively isolate, and functionally characterize the quiescent stem-like cells, we identify a label-retaining cell (LRC) population in the mouse prostate luminal cell layer as candidate luminal progenitors. Through comprehensive molecular and biological characterizations, we show that these luminal LRCs exhibit relative dormancy with significant enrichment in the mouse proximal prostate, display bipotent potential in both in vitro organoid formation and the in vivo prostate regeneration assay, express a stem/progenitor gene signature with resemblance to aggressive prostate cancer. Importantly, these luminal LRCs maintain a lower level of Ar expression, are androgen-independent, and resist castration in vivo. Furthermore, analysis of phenotypic markers by immunefluorescent staining reveals heterogeneity within luminal progenitor cell pool. Collectively, our studies establish luminal LRCs as progenitors that may serve as a cellular origin for castration resistant prostate cancer.
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Project description:We performed gene expression microarray comparing Ly6D- CLPs isolated from OcnCre;iDTR control and mutant mice by flow cytometry. Ly6D- CLPs were isolated from the bone marrow of OcnCre;iDTR control or mutant mice by flow cytometry and subjected to Affymetrix microarray comparison of gene expression. Markers used to define Ly6D- CLP by flow cytometry was: LineageLo, cKit+, Sca+, CD127+, Thy1.2-, Ly6D-
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Project description:One of the major hurdles for the early detection of cancer is our poor understanding of tumour initiating events. Historically, cancer research has focused on histological and molecular characterisation of established tumours, which has led to the identification of hundreds of putative driver mutations. It is currently unclear how these genetic aberrations impact the cell state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) for example has been shown to arise from luminal progenitor cells1,2 yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that the perturbation of Brca1/p53 in luminal progenitors induces an aberrant alveolar differentiation pre-malignancy. Unlike alveolar differentiation occurring during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Our experimental approach has allowed us to further identify responses in the stromal and immune cell compartments during the early steps of tumourigenesis. Based on our data we propose a model where transcriptional and epigenetic changes driven by Brca1/p53 inadvertently promote a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell of origin and offering a potential explanation for the tissue specificity of BRCA1 tumours. Moving forward, the phenotype identified herein should be evaluated as a target for early detection and treatment of TNBC.
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2011-11-22 | E-GEOD-27402 | biostudies-arrayexpress
Project description:One of the major hurdles for the early detection of cancer is our poor understanding of tumour initiating events. Historically, cancer research has focused on histological and molecular characterisation of established tumours, which has led to the identification of hundreds of putative driver mutations. It is currently unclear how these genetic aberrations impact the cell state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) for example has been shown to arise from luminal progenitor cells yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that the perturbation of Brca1/p53 in luminal progenitors induces an aberrant alveolar differentiation pre-malignancy. Unlike alveolar differentiation occurring during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Our experimental approach has allowed us to further identify responses in the stromal and immune cell compartments during the early steps of tumourigenesis. The data in this repository contains the human bulk RNA-sequencing that was presented as part of this study.
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Project description:Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. We use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra- proximal stem/progenitor cells.
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Project description:Single-cell RNA-sequencing has emerged as a powerful technology to assess heterogeneity within defined cell populations. Here, we comprehensively study the heterogeneity of a previously described B220+CD117intCD19-NK1.1- uncommitted hematopoietic progenitor with combined lymphoid and myeloid potential (EPLM). Using staining for surface markers together with functional assays, we describe four subpopulations of this progenitor with distinct lineage developmental potentials. Amongst them, the Ly6D+SiglecH-CD11c- fraction was lymphoid restricted exhibiting strong B-cell potential, whereas the Ly6D-SiglecH-CD11c- fraction showed mixed lympho-myeloid potential. Single-cell RNA-sequencing of these subsets revealed that the latter population is composed of a mixture of cells with distinct lymphoid and myeloid genetic signatures and identified a subgroup as the potential precursor of Ly6D+SiglecH-CD11c-. We observed a B-cell priming gradient within the Ly6D+SiglecH-CD11c- subset and propose a herein newly identified subgroup as the direct precursor of the first B-cell committed stage. Our study demonstrates that the multipotency of B220+CD117intCD19-NK1.1- progenitors is a result of underlying heterogeneity at the single-cell level. Moreover, it highlights the validity of single-cell transcriptomics to resolve cellular heterogeneity and identify developmental relationships in hematopoietic progenitors.
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