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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Karsten Bach
  • Sara Pensa
  • Marija Zarocsinceva
  • Katarzyna Kania
  • Julie Stockis
  • Silvain Pinaud
  • Kyren A. Lazarus
  • Mona Shehata
  • Alice R. Greenhalgh
  • Carlos Caldas
  • Timotheus Y. F. Halim
  • John C. Marioni
  • Walid T. Khaled

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.

Bibliographical metadata

Original languageEnglish
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 9 Mar 2021