Pre-neoplastic stromal cells drive BRCA1-mediated breast tumorigenesis
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PROVIDER: PRJNA730582 | ENA |
REPOSITORIES: ENA
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Project description:Women with germline mtuation in BRCA1 have increased risk for developing hereditary breast cancer. The role of the epitheilum-assocaited niche during BRCA1-driven tumor intiation remains unclear. Here, we show that the pre-malignant stromal niche promotes epithelial prolifeation and BRCA1-driven cancer intiation in trans. Using single-cell RNA seq analysis of human pre-neoplastic BRCA1 and control breast tissue, we show that stromal cells provide numerous pro-proliferative paracrine signals inducing epithelial proliferation.
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Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie Dropseq.
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2012-07-23 | E-GEOD-32905 | biostudies-arrayexpress
Project description:Brca1 mutation predisposes women to early onset of breast and ovarian cancers.Through its diverse functions in DNA damage repair, cell cycle control, transcription regulation, ubiquitination and so on, BRCA1 acts as a very significant tumor suppressor and genomic safeguard. Brca1 deficiency induces severe cellular stress, when occurring in the mammary glands, it impairs the regular developmental process and eventually causes tumorigenesis due to accumulation of genome instability and other mechanisms. The Brca1-defiencient mouse mammary tumor were characterized with great tumoral heterogeneity, which is in line with the human breast cancers carrying BRCA1 mutations. Here we studied the molecular complexicity of Brca1-deficient mouse mammary tumors vie single cell RNA sequencing.
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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.
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Project description:In pancreatic cancer, select cells within a homogeneous epithelium drive tumorigenesis in response to an environmental trigger, suggesting key uncharacterized roles for epigenetics and cellular context. To investigate epigenetic plasticity in early tumorigenesis, we performed single-cell transcriptional and chromatin accessibility sequencing of Kras-mutant pancreatic cancer models, encompassing initiation to malignant stages and wild-type tissue. Our analysis identifies a few progenitor states that correspond to known cells-of-origin, exhibit the greatest measured epigenetic plasticity, and are primed for diverse neoplastic fates. Plasticity is strongly associated with accessibility near receptor and ligand loci. We delineated robust communication modules and a feedback loop between IL33-expressing epithelial and immune cells with broad tissue impacts, which we confirmed by genetic perturbation in mice. Our results promise to nominate early interception strategies for this lethal cancer.
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Project description:In pancreatic cancer, select cells within a homogeneous epithelium drive tumorigenesis in response to an environmental trigger, suggesting key uncharacterized roles for epigenetics and cellular context. To investigate epigenetic plasticity in early tumorigenesis, we performed single-cell transcriptional and chromatin accessibility sequencing of Kras-mutant pancreatic cancer models, encompassing initiation to malignant stages and wild-type tissue. Our analysis identifies a few progenitor states that correspond to known cells-of-origin, exhibit the greatest measured epigenetic plasticity, and are primed for diverse neoplastic fates. Plasticity is strongly associated with accessibility near receptor and ligand loci. We delineated robust communication modules and a feedback loop between IL33-expressing epithelial and immune cells with broad tissue impacts, which we confirmed by genetic perturbation in mice. Our results promise to nominate early interception strategies for this lethal cancer.
2023-04-27 | GSE207698 | GEO
Project description:In pancreatic cancer, select cells within a homogeneous epithelium drive tumorigenesis in response to an environmental trigger, suggesting key uncharacterized roles for epigenetics and cellular context. To investigate epigenetic plasticity in early tumorigenesis, we performed single-cell transcriptional and chromatin accessibility sequencing of Kras-mutant pancreatic cancer models, encompassing initiation to malignant stages and wild-type tissue. Our analysis identifies a few progenitor states that correspond to known cells-of-origin, exhibit the greatest measured epigenetic plasticity, and are primed for diverse neoplastic fates. Plasticity is strongly associated with accessibility near receptor and ligand loci. We delineated robust communication modules and a feedback loop between IL33-expressing epithelial and immune cells with broad tissue impacts, which we confirmed by genetic perturbation in mice. Our results promise to nominate early interception strategies for this lethal cancer.
2023-04-27 | GSE207920 | GEO
Project description:SUMMARY Medulloblastoma is the most common malignant brain tumor in children. It is thought to result from transformation of granule cell precursors (GCPs) in the developing cerebellum, but little is known about the early stages of the disease. Here we identify a pre-neoplastic stage of medulloblastoma in patched heterozygous mice, a model of the human disease. We show that pre-neoplastic cells are present in the majority of patched mutants, although only 16% of these mice develop tumors. Pre-neoplastic cells, like tumor cells, exhibit activation of the Sonic hedgehog pathway and constitutive proliferation. Importantly, they also lack expression of the wild-type patched allele, suggesting that loss of patched is an early event in tumorigenesis. While pre-neoplastic cells resemble GCPs and tumor cells in many respects, they have a distinct molecular signature. Genes that mark the pre-neoplastic stage include regulators of migration, apoptosis and differentiation, processes critical for normal development but previously unrecognized for their role in medulloblastoma. The identification and molecular characterization of pre-neoplastic cells provides insight into the early steps in medulloblastoma formation, and may yield important markers for early detection and therapy of this disease. ANIMALS Patched heterozygous mice (Goodrich et al., 1997) were obtained from Matthew Scott's lab at Stanford, and maintained by breeding with 129X1/SvJ mice from Jackson Laboratories. Math1-GFP transgenic mice (Lumpkin et al., 2003) were provided by Jane Johnson at UT Southwestern Medical Center. Math1-GFP/patched+/- mice were generated by crossing patched heterozygotes with Math1-GFP mice, and then backcrossing to Math1-GFP mice three times before further analysis. All mice were maintained in the Cancer Center Isolation Facility at Duke University Medical Center. ISOLATION OF CELLS Granule cell precursors (GCPs) were isolated from 7-day-old (P7) patched+/- mice; preneoplastic cells were obtained from 6 week-old patched mutants; and tumor cells were obtained from 10-25-week old patched mutants displaying physical and behavioral signs of medulloblastoma. Cells were isolated from each source using a protocol described in (Wechsler- Reya and Scott, 1999). Briefly, cerebella were digested in solution containing 10 U/ml papain Oliver et al. Pre-Neoplastic Stage of Medulloblastoma - 8 - (Worthington, Lakewood, NJ) and 250 U/ml DNase (Sigma) and triturated to obtain a cell suspension. This suspension was centrifuged through a step gradient of 35% and 65% Percoll (Amersham Biosciences, Piscataway, NJ), and cells were harvested from the 35%-65% interface. Cells were resuspended in serum-free culture medium consisting of Neurobasal containing B27 supplement, sodium pyruvate, L-glutamine, and penicillin/streptomycin (all from Invitrogen, Carlsbad, California) and counted on a hemacytometer. Cells used for RNA isolation were centrifuged and flash frozen in liquid nitrogen. For proliferation assays or immunostaining, cells were plated on poly-D-lysine (PDL)-coated tissue culture vessels and incubated in serum-free culture medium. MICROARRAY HYBRIDIZATION AND ANALYSIS RNA from GCPs, pre-neoplastic cells and tumor cells (isolated as described above, but not FACS-sorted) and from normal adult cerebellum (not dissociated) was converted to cDNA using the Superscript Choice cDNA kit (Invitrogen) and a T7-dT(24) primer (Genset/Proligo, Boulder, CO). cRNA was generated using a T7-transcription/labeling kit from Enzo Life Sciences and hybridized to Affymetrix U74Av2 chips (Affymetrix, Santa Clara, CA). Chips were scanned, and hybridization data were acquired using Affymetrix Suite 5.0 software. Affymetrix CEL files were normalized and quantified using Bioconductor software with the gcRMA model to quantify gene expression levels (Gentleman and Carey, 2002). Unsupervised principal components analysis (PCA) was used to identify the relationships among normal adult cerebellum, GCPs, pre-neoplastic cells and tumor cells based on expression profiles. To identify genes that were differentially expressed among GCPs, pre-neoplastic cells and tumor cells, supervised analysis was carried out. A gene-by-gene ANOVA model with three groups (GCP, pre-neoplastic, tumor) was used to fit the log2-transformed intensities. To correct for multiple comparisons, the nominal p-value was adjusted using the false discovery rate (Benjamini and Hochberg, 1995). Genes were considered to be differentially expressed if they satisfied all of the following criteria: a difference in expression greater than 1.9-fold between any two groups, a maximum absolute intensity difference larger than 32 units, and an adjusted pvalue < 0.01. There were 118 genes that met these criteria. The identities of differentially expressed genes were verified by integrating data from the Affymetrix and Unigene databases. Gene functions were determined using information from Gene Ontology, Unigene, LocusLink and PubMed databases. Clustering was performed with Cluster and Treeview (Eisen et al., 1998). All statistical analysis was performed using R-1.7 software (Dalgaard, 2002). Results were visualized with Spotfire 6.0 (Somerville, MA). CORRESPONDING AUTHOR Robert J. Wechsler-Reya* Dept. of Pharmacology & Cancer Biology, Duke University Medical Center Box 3813, Durham, NC 27710 Phone: 919-613-8754. Fax: 919-668-3556. Email: rw.reya@duke.edu Keywords = medulloblastoma Keywords = brain tumor Keywords = pre-neoplastic Keywords = patched Keywords = hedgehog Keywords = migration Keywords = differentiation
2005-03-22 | GSE2426 | GEO