Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

Karsten Bach, Sara Pensa, Marija Zarocsinceva, Katarzyna Kania, Julie Stockis, Silvain Pinaud, Kyren A. Lazarus, Mona Shehata, Bruno M. Simões, Alice R. Greenhalgh, Sacha J. Howell, Robert B. Clarke, Carlos Caldas, Timotheus Y. F. Halim, John C. Marioni () and Walid T. Khaled ()
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Karsten Bach: Department of Pharmacology
Sara Pensa: Department of Pharmacology
Marija Zarocsinceva: Cambridge Cancer Centre
Katarzyna Kania: University of Cambridge
Julie Stockis: University of Cambridge
Silvain Pinaud: University of Cambridge
Kyren A. Lazarus: Department of Pharmacology
Mona Shehata: University of Cambridge
Bruno M. Simões: University of Manchester
Alice R. Greenhalgh: University of Manchester
Sacha J. Howell: University of Manchester
Robert B. Clarke: University of Manchester
Carlos Caldas: University of Cambridge
Timotheus Y. F. Halim: University of Cambridge
John C. Marioni: University of Cambridge
Walid T. Khaled: Department of Pharmacology

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21783-3

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DOI: 10.1038/s41467-021-21783-3

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