Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors
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ABSTRACT:
PROVIDER: PRJEB42740 | ENA |
REPOSITORIES: ENA
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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.
2021-02-02 | E-MTAB-10043 | 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.
2021-02-02 | E-MTAB-10046 | biostudies-arrayexpress
Project description:Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors
| PRJEB42740 | ENA
Project description:Time-resolved single-cell analysis of Brca1 associated mammary tumorigenesis reveals aberrant differentiation of luminal progenitors
| PRJEB42689 | ENA
Project description:It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors 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 perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes 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.
| S-EPMC7940427 | biostudies-literature
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC.
2019-06-27 | GSE114787 | GEO
Project description:The mammary epithelia are mainly composed of two distinct lineages, the basal and luminal cells. In our MMTV-Cre; Brca1flox/flox mouse model, we found the Brca1 knockout mainly occurred in the luminal cells, which will lead the mammary tumorigenesis. To investigate the Brca1 deficiency mediated mammary tumorigenesis, we sorted the luminal cells from wild type mice and MMTV-Cre; Brca1flox/flox mice for RNAseq analysis.
2021-11-17 | GSE148613 | GEO
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre one month after the intraductal injection.
2019-06-27 | GSE126761 | GEO
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre at different time points after the intraductal injection, as well as mammary tumors developed in this model, by single cell expression analysis.
2019-06-27 | GSE130453 | GEO
Project description:Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in DNA repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. Cell culture-based studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcriptional regulation and genetic instability. We found that BRCA1 mutation-associated R-loop accumulates preferentially in luminal epithelial cells of cancer-free human breast tissue, and at the 5' end of those genes that experience promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of mouse NELF-B/COBRA1, a Pol II-pausing factor and BRCA1-binding protein, in Brca1 knockout mouse mammary epithelium ameliorates R-loop accumulation and reduces mammary tumorigenesis. Our studies show that Pol II pausing is a previously unappreciated contributor to BRCA1-associated R-loop accumulation and breast cancer development.
2017-06-27 | GSE96672 | GEO