Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors
| العنوان: | Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors |
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| المؤلفون: | Silvain Pinaud, Karsten Bach, Marija Zarocsinceva, Sacha J Howell, Sara Pensa, Carlos Caldas, Katarzyna D. Kania, Bruno M Simões, John C. Marioni, Alice R. Greenhalgh, Julie Stockis, Mona Shehata, Walid T. Khaled, Kyren A. Lazarus, Timotheus Y.F. Halim, Robert Clarke |
| المساهمون: | Zarocsinceva, Marija [0000-0001-6015-3656], Stockis, Julie [0000-0003-4911-6891], Simões, Bruno M. [0000-0003-1253-6657], Howell, Sacha J. [0000-0001-8141-6515], Clarke, Robert B. [0000-0001-5407-3123], Caldas, Carlos [0000-0003-3547-1489], Halim, Timotheus Y. F. [0000-0001-9773-0023], Khaled, Walid T. [0000-0001-9068-5776], Apollo - University of Cambridge Repository, Simões, Bruno M [0000-0003-1253-6657], Howell, Sacha J [0000-0001-8141-6515], Clarke, Robert B [0000-0001-5407-3123], Halim, Timotheus YF [0000-0001-9773-0023], Khaled, Walid T [0000-0001-9068-5776] |
| المصدر: | Bach, K, Pensa, S, Zarocsinceva, M, Kania, K, Stockis, J, Pinaud, S, Lazarus, K A, Shehata, M, Simões, B M, Greenhalgh, A R, Howell, S J, Clarke, R B, Caldas, C, Halim, T Y F, Marioni, J C & Khaled, W T 2021, ' Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors ', Nature Communications, vol. 12, no. 1 . https://doi.org/10.1038/s41467-021-21783-3 Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, endocrine system diseases, Cellular differentiation, General Physics and Astronomy, Cell Communication, medicine.disease_cause, Mice, 0302 clinical medicine, Breast cancer, Single-cell analysis, Cancer genomics, Tumor Microenvironment, skin and connective tissue diseases, 49/91, Mutation, Multidisciplinary, Manchester Cancer Research Centre, BRCA1 Protein, Stem Cells, article, Cell Differentiation, Cell biology, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Phenobarbital, Female, Stem cell, Single-Cell Analysis, Cell signaling, Science, Breast Neoplasms, 631/67/69, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, Progenitor cell, Transcription factor, Tumor microenvironment, ResearchInstitutes_Networks_Beacons/mcrc, Mammary Neoplasms, Experimental, General Chemistry, 631/67/1347, 64/110, 030104 developmental biology, Tumor Suppressor Protein p53 |
| الوصف: | 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. BRCA1 driven breast cancer arises from luminal progenitor cells but how BRCA1 loss-of-function affects the luminal progenitor cell state during premalignant stages of the disease is still unclear. Here, the authors demonstrate an aberrant differentiation of luminal progenitors towards a partial secretory luminal cell phenotype that occurs in a Brca1 deficient mouse model of breast cancer at early stages of tumour initiation and in breast cells from BRCA1 carriers. |
| وصف الملف: | application/zip; text/xml; application/pdf |
| DOI: | 10.17863/cam.64705 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::24be004e59da16b4cf960b7624ca74bc |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....24be004e59da16b4cf960b7624ca74bc |
| قاعدة البيانات: | OpenAIRE |
| DOI: | 10.17863/cam.64705 |
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