E-Poster Presentation 33rd Lorne Cancer Conference 2021

Epigenome erosion and neural crest-like phenotypic reprogramming in triple-negative breast cancer (#193)

Jodi M Saunus 1 , Xavier M De Luca 1 , Korinne Northwood 1 2 , Ashwini Raghavendra 1 , Alexander Hasson 3 , Amy E McCart Reed 1 , Malcolm Lim 1 , Samir Lal 1 , Ana Cristina Vargas 1 , Jamie R Kutasovic 1 , Andrew J Dalley 1 , Mariska Miranda 4 , Emarene Kalaw 1 , Priyakshi Kalita-de Croft 1 , Irma Gresshoff 1 , Fares Al-Ejeh 4 , Kum Kum Khanna 4 , Jonathan Beesley 4 , Georgia Chenevix Trench 4 , Andrew R Green 5 , Emad A Rakha 5 , Ian O Ellis 5 , Melissa A Brown 2 , Peter T Simpson 1 , Dan V Nicolau Jr. 3 6 , Sunil R Lakhani 1 7
  1. Faculty of Medicine, UQ Centre for Clinical Research, The University of Queensland, Herston, Qld, Australia
  2. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Qld, Australia
  3. School of Mathematical Sciences and ARC Centre of Excellence for Mathematical and Statistical Frontiers, Queensland University of Technology, Brisbane, Qld, Australia
  4. QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia
  5. Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, The University of Nottingham, Nottingham, UK
  6. Mathematical Institute, The University of Oxford, Oxford, UK
  7. Pathology Queensland, Herston, Qld, Australia

Intratumoural heterogeneity is a hindrance to the effective treatment of triple-negative breast cancer (TNBC). TNBC cells are inherently plastic and can adopt heritable, drug-tolerant phenotypic states in response to treatment. We investigated the role of stem cell specifier SOX10 to phenotypic plasticity in TNBC by immuno-phenotyping large, annotated breast tissue sample cohorts (1860 tumours, 21 cosmetic reductions), and then developed a systems-level analysis strategy to contextualise SOX10’s TNBC-specific regulatory circuit.

Nuclear SOX10 was detected in luminal progenitor cells of the mammary gland (TNBC's ostensible normal cellular precursor). In the tumour cohort, SOX10 nuclear staining was specific for TNBC (34.7% positive compared to 1.3% of non-TN; p=1.1E-91; Chi-square test); and was a robust indicator of shorter disease-specific survival in this patient group (p=0.0026; log-rank test), with prognostic significance independent of tumour size, young age at diagnosis (≤40 yr) and the density of tumour-infiltrating lymphocytes (p<0.05; Cox regression model).

To investigate the biological basis of this, we performed systems-level network analysis of high-dimensional breast cancer omics datasets to map SOX10’s gene regulatory module within the TNBC transcriptome and identify its drivers. We show that SOX10’s module confers a transcriptionally related state to neural crest stem cells (NCSCs), even after applying stringent noise-correction algorithms to the network. Other findings suggest that this program evolves from the mammary luminal progenitor transcriptome as the demand for DNA repair drives progressive erosion of breast lineage-specific epigenetic marks (promoter CpG island shores), simulating a more primitive epigenome. Applying the pipeline in other cancer types revealed similarly strong NCSC signals in melanomas and gliomas, which both express SOX10, derive from SOX10-expressing cellular precursors and have broadly eroded epigenomes.

We propose that on the expanded chromatin landscape of high-grade cancers, developmental fate specifiers like SOX10 recreate their ancestral regulatory circuits by default. These findings provide new insights about the basis of TNBC heterogeneity and underscore the potential for therapeutics that limit chromatin remodelling.