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

Author

Listed:
  • Karsten Bach

    (Department of Pharmacology
    University of Cambridge
    Cambridge Cancer Centre)

  • Sara Pensa

    (Department of Pharmacology
    Cambridge Cancer Centre)

  • Marija Zarocsinceva

    (Cambridge Cancer Centre
    Wellcome-MRC Cambridge Stem Cell Institute)

  • Katarzyna Kania

    (University of Cambridge)

  • Julie Stockis

    (University of Cambridge)

  • Silvain Pinaud

    (University of Cambridge)

  • Kyren A. Lazarus

    (Department of Pharmacology
    Cambridge Cancer Centre)

  • Mona Shehata

    (University of Cambridge)

  • Bruno M. Simões

    (University of Manchester)

  • Alice R. Greenhalgh

    (University of Manchester)

  • Sacha J. Howell

    (University of Manchester
    Christie NHS Foundation Trust)

  • Robert B. Clarke

    (University of Manchester)

  • Carlos Caldas

    (University of Cambridge
    Cambridge Cancer Centre)

  • Timotheus Y. F. Halim

    (University of Cambridge)

  • John C. Marioni

    (University of Cambridge
    Wellcome Genome Campus, Hinxton
    European Molecular Biology Laboratory)

  • Walid T. Khaled

    (Department of Pharmacology
    Cambridge Cancer Centre
    Wellcome-MRC Cambridge Stem Cell Institute)

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.

Suggested Citation

  • 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 , 2021. "Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21783-3
    DOI: 10.1038/s41467-021-21783-3
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    Cited by:

    1. Zhengcheng He & Ryan Ghorayeb & Susanna Tan & Ke Chen & Amanda C. Lorentzian & Jack Bottyan & Syed Mohammed Musheer Aalam & Miguel Angel Pujana & Philipp F. Lange & Nagarajan Kannan & Connie J. Eaves , 2022. "Pathogenic BRCA1 variants disrupt PLK1-regulation of mitotic spindle orientation," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Maryam Ghaderi Najafabadi & G. Kenneth Gray & Li Ren Kong & Komal Gupta & David Perera & Huw Naylor & Joan S. Brugge & Ashok R. Venkitaraman & Mona Shehata, 2023. "A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Francesca Mateo & Zhengcheng He & Lin Mei & Gorka Ruiz de Garibay & Carmen Herranz & Nadia García & Amanda Lorentzian & Alexandra Baiges & Eline Blommaert & Antonio Gómez & Oriol Mirallas & Anna Garri, 2022. "Modification of BRCA1-associated breast cancer risk by HMMR overexpression," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    4. Elena Spina & Julia Simundza & Angela Incassati & Anupama Chandramouli & Matthias C. Kugler & Ziyan Lin & Alireza Khodadadi-Jamayran & Christine J. Watson & Pamela Cowin, 2022. "Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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