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

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

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Authors

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 Beesley

Georgia Chenevix-Trench

EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology

Dan V. Nicolau

Peter T. Simpson

Sunil R. Lakhani



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.

Journal Article Type Article
Acceptance Date Mar 29, 2022
Online Publication Date May 2, 2022
Publication Date May 2, 2022
Deposit Date Apr 6, 2022
Publicly Available Date May 4, 2022
Journal npj Breast Cancer
Electronic ISSN 2374-4677
Peer Reviewed Peer Reviewed
Volume 8
Issue 1
Article Number 57
DOI https://doi.org/10.1038/s41523-022-00425-x
Public URL https://nottingham-repository.worktribe.com/output/7709767
Publisher URL https://www.nature.com/articles/s41523-022-00425-x

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