Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer

Jodi M. Saunus*, Xavier M. De Luca, Korinne Northwood, Ashwini Raghavendra, Alexander Hasson, Amy E. McCart Reed, Malcolm Lim, Samir Lal, A. Cristina Vargas, Jamie R. Kutasovic, Andrew J. Dalley, Mariska Miranda, Emarene Kalaw, Priyakshi Kalita-de Croft, Irma Gresshoff, Fares Al-Ejeh, Julia M.W. Gee, Chris Ormandy, Kum Kum Khanna, Jonathan BeesleyGeorgia Chenevix-Trench, Andrew R. Green, Emad A. Rakha, Ian O. Ellis, Dan V. Nicolau, Peter T. Simpson, Sunil R. Lakhani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Intratumoral heterogeneity is caused by genomic instability and phenotypic plasticity, but how these features co-evolve remains unclear. SOX10 is a neural crest stem cell (NCSC) specifier and candidate mediator of phenotypic plasticity in cancer. We investigated its relevance in breast cancer by immunophenotyping 21 normal breast and 1860 tumour samples. Nuclear SOX10 was detected in normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In tumours, nuclear SOX10 was almost exclusive to TNBC, and predicted poorer outcome amongst cross-sectional (p = 0.0015, hazard ratio 2.02, n = 224) and metaplastic (p = 0.04, n = 66) cases. To understand SOX10’s influence over the transcriptome during the transition from normal to malignant states, we performed a systems-level analysis of co-expression data, de-noising the networks with an eigen-decomposition method. This identified a core module in SOX10’s normal mammary epithelial network that becomes rewired to NCSC genes in TNBC. Crucially, this reprogramming was proportional to genome-wide promoter methylation loss, particularly at lineage-specifying CpG-island shores. We propose that the progressive, genome-wide methylation loss in TNBC simulates more primitive epigenome architecture, making cells vulnerable to SOX10-driven reprogramming. This study demonstrates potential utility for SOX10 as a prognostic biomarker in TNBC and provides new insights about developmental phenotypic mimicry—a major contributor to intratumoral heterogeneity.

Original languageEnglish
Article number57
Number of pages16
Journalnpj Breast Cancer
Volume8
Issue number1
DOIs
Publication statusPublished - 2 May 2022
Externally publishedYes

Keywords

  • Brca1
  • Cell-lines
  • Differentiation
  • Epithelial progenitors
  • Evolution
  • Heterogeneity
  • Metastasis
  • Predictor
  • Reveals
  • Stem-cells

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