Epigenome erosion drives neural crest-like phenotypic mimicry in triple-negative breast cancer and other SOX10+ malignancies

Background Intratumoural heterogeneity is a poor prognostic feature in triple-negative breast cancer (TNBC) and other high-grade malignancies. It is caused by genomic instability and phenotypic plasticity, but how these features co-evolve during tumour development remains unclear. SOX10 is a transcription factor, neural crest stem cell (NCSC) specifier and candidate mediator of cancer-associated phenotypic plasticity. Methods Using immunophenotyping, we investigated the expression of SOX10 in normal human breast tissue and breast cancer (n=21 cosmetic breast reduction and 1,860 tumour samples with clinical annotation). We then defined the context and evolution of its expression in TNBC compared to 21 other malignancies using systems-level transcriptomics. Results SOX10 was detected in nuclei of normal mammary luminal progenitor cells, the histogenic origin of most TNBCs. In breast cancer, nuclear SOX10 predicted poor outcome amongst cross-sectional (log-rank p=0.0015, hazard ratio 2.02, n=224) and metaplastic (log-rank p=0.04, n=66) TNBCs. Systems-level transcriptional network analysis identified a core module in SOX10’s normal mammary epithelial transcription program that is rewired to NCSC genes in TNBC. Reprogramming was proportional to DNA damage and genome-wide promoter hypomethylation, particularly at CpG island shores. Using a novel network analysis pipeline, we found that NCSC-like transcriptional reprogramming is also strongly associated with promoter hypomethylation in other SOX10+ malignancies: glioma and melanoma. Conclusions We propose that cancer-associated genome hypomethylation simulates the open chromatin landscape of more primitive cell states, and that on this relatively unrestricted background, SOX10 recreates its ancestral gene regulatory circuits by default. These findings provide new insights about the basis of intratumoural heterogeneity and resurrection of developmental phenotypes in cancer; and highlight the potential for therapeutics that limit chromatin remodelling.

[1]  C. Scafoglio,et al.  Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer , 2020, Cancers.

[2]  M. Wegner,et al.  The transcription factor Sox10 is an essential determinant of branching morphogenesis and involution in the mouse mammary gland , 2020, Scientific Reports.

[3]  Qing Zhang,et al.  BBOX1 promotes triple-negative breast cancer progression by controlling IP3R3 stability , 2020, Molecular & cellular oncology.

[4]  O. Harb,et al.  TFAP2B, AP-1 and JAZF1 Expression in Tissues of Papillary Thyroid Carcinoma Patients; Clinical, Pathological and Prognostic Values , 2020, Asian Pacific Journal of Cancer Prevention.

[5]  Ola A Harb,et al.  TFAP2B, AP-1 and JAZF1 Expression in Tissues of Papillary Thyroid Carcinoma Patients; Clinical, Pathological and Prognostic Values. , 2020, Asian Pacific journal of cancer prevention : APJCP.

[6]  Laura E. Herring,et al.  Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer. , 2020, Cancer discovery.

[7]  B. Haibe-Kains,et al.  Epigenetic switch-induced viral mimicry evasion in chemotherapy resistant breast cancer. , 2020, Cancer discovery.

[8]  Jian-hua Zhou,et al.  SOX10 – A Novel Marker for the Differential Diagnosis of Breast Metaplastic Squamous Cell Carcinoma , 2020, Cancer management and research.

[9]  Charles C. Bell,et al.  Principles and mechanisms of non-genetic resistance in cancer , 2019, British Journal of Cancer.

[10]  J. Seidman,et al.  DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging , 2019, bioRxiv.

[11]  Andreas R. Pfenning,et al.  Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals , 2019, bioRxiv.

[12]  C. Eaves,et al.  Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer , 2019, The EMBO journal.

[13]  K. Polyak,et al.  Intratumoral Heterogeneity: More Than Just Mutations. , 2019, Trends in cell biology.

[14]  Jamie R. Kutasovic,et al.  Phenotypic and molecular dissection of metaplastic breast cancer and the prognostic implications , 2018, The Journal of pathology.

[15]  M. Hoffman,et al.  Sox10 Regulates Plasticity of Epithelial Progenitors toward Secretory Units of Exocrine Glands , 2019, Stem cell reports.

[16]  Piyush B. Gupta,et al.  Phenotypic Plasticity: Driver of Cancer Initiation, Progression, and Therapy Resistance. , 2019, Cell stem cell.

[17]  Dan Zhou,et al.  BCL11A enhances stemness and promotes progression by activating Wnt/β-catenin signaling in breast cancer , 2019, Cancer management and research.

[18]  Anton Simeonov,et al.  KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. , 2018, Cancer cell.

[19]  Melissa J. Davis,et al.  Single sample scoring of molecular phenotypes , 2018, BMC Bioinformatics.

[20]  Margaret P. Chapman,et al.  Differentiation-state plasticity is a targetable resistance mechanism in basal-like breast cancer , 2018, Nature Communications.

[21]  A. Regev,et al.  Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer. , 2018, Cell reports.

[22]  G. Wahl,et al.  Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity. , 2018, Cancer cell.

[23]  B. Lin,et al.  Modulating Cell Fate as a Therapeutic Strategy. , 2018, Cell stem cell.

[24]  J. Issa,et al.  TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer. , 2018, Cancer research.

[25]  S. Lakhani,et al.  The Brisbane Breast Bank , 2018 .

[26]  Hui Shen,et al.  DNA methylation loss in late-replicating domains is linked to mitotic cell division , 2018, Nature Genetics.

[27]  P. Fasching,et al.  Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. , 2018, The Lancet. Oncology.

[28]  J. Gustafsson,et al.  Intratumor heterogeneity predicts metastasis of triple-negative breast cancer , 2017, Carcinogenesis.

[29]  William A. Flavahan,et al.  Epigenetic plasticity and the hallmarks of cancer , 2017, Science.

[30]  G. Wahl,et al.  Cell state plasticity, stem cells, EMT, and the generation of intra-tumoral heterogeneity , 2017, npj Breast Cancer.

[31]  E. Birney,et al.  HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures , 2017, Nature Medicine.

[32]  Mei Liu,et al.  Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  W. Yarbrough,et al.  Expression Profiling of Clinical Specimens Supports the Existence of Neural Progenitor‐Like Stem Cells in Basal Breast Cancers , 2017, Clinical breast cancer.

[34]  Jie Huang,et al.  Knockdown of SOX9 Inhibits the Proliferation, Invasion, and EMT in Thyroid Cancer Cells. , 2017, Oncology research.

[35]  N. Pollet,et al.  Implication of thyroid hormone signaling in neural crest cells migration: Evidence from thyroid hormone receptor beta knockdown and NH3 antagonist studies , 2017, Molecular and Cellular Endocrinology.

[36]  Jamie R. Kutasovic,et al.  Multidimensional phenotyping of breast cancer cell lines to guide preclinical research , 2017, Breast Cancer Research and Treatment.

[37]  Steven J. M. Jones,et al.  Analysis of Normal Human Mammary Epigenomes Reveals Cell-Specific Active Enhancer States and Associated Transcription Factor Networks. , 2016, Cell reports.

[38]  Funda Meric-Bernstam,et al.  Punctuated Copy Number Evolution and Clonal Stasis in Triple-Negative Breast Cancer , 2016, Nature Genetics.

[39]  David C. Jones,et al.  Landscape of somatic mutations in 560 breast cancer whole genome sequences , 2016, Nature.

[40]  G. Wahl,et al.  Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells. , 2015, Cell reports.

[41]  Eytan Domany,et al.  Pathway‐based personalized analysis of breast cancer expression data , 2015, Molecular oncology.

[42]  Rezvan Ehsani,et al.  EpiFactors: a comprehensive database of human epigenetic factors and complexes , 2015, Database J. Biol. Databases Curation.

[43]  J. Kopczyński,et al.  Sox10—A Marker for Not Only Schwannian and Melanocytic Neoplasms But Also Myoepithelial Cell Tumors of Soft Tissue: A Systematic Analysis of 5134 Tumors , 2015, The American journal of surgical pathology.

[44]  Andrew Menzies,et al.  Subclonal diversification of primary breast cancer revealed by multiregion sequencing , 2015, Nature Medicine.

[45]  Rodney J Scott,et al.  Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value , 2015, Nature Communications.

[46]  A. Errico.  Genetics: BCL11A—targeting triple-negative breast cancer? , 2015, Nature Reviews Clinical Oncology.

[47]  M. Bronner,et al.  Establishing neural crest identity: a gene regulatory recipe , 2015, Development.

[48]  Sajjad Karim,et al.  Comparison of microarray expression profiles between follicular variant of papillary thyroid carcinomas and follicular adenomas of the thyroid , 2015, BMC Genomics.

[49]  S. Chin,et al.  BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells , 2015, Nature Communications.

[50]  M. Bronner,et al.  DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10 , 2014, Proceedings of the National Academy of Sciences.

[51]  Xinzhong Dong,et al.  Generation of multipotent induced neural crest by direct reprogramming of human postnatal fibroblasts with a single transcription factor. , 2014, Cell stem cell.

[52]  Gordon B Mills,et al.  Comprehensive Genomic Analysis Identifies Novel Subtypes and Targets of Triple-Negative Breast Cancer , 2014, Clinical Cancer Research.

[53]  Winston Timp,et al.  Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors , 2014, Genome Medicine.

[54]  N. Navin,et al.  Clonal Evolution in Breast Cancer Revealed by Single Nucleus Genome Sequencing , 2014, Nature.

[55]  Y. Liu,et al.  FGF signaling activates a Sox9-Sox10 pathway for the formation and branching morphogenesis of mouse ocular glands , 2014, Development.

[56]  David T. W. Jones,et al.  Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing , 2014, Nature.

[57]  Rochelle L. Tiedemann,et al.  Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells , 2014, Genome Biology.

[58]  J. Visvader,et al.  Mammary stem cells and the differentiation hierarchy: current status and perspectives , 2014, Genes & development.

[59]  J. Issa,et al.  TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells , 2014, Nucleic acids research.

[60]  I. Antoshechkin,et al.  Transcriptome analysis reveals novel players in the cranial neural crest gene regulatory network , 2014, Genome research.

[61]  Laura M. Heiser,et al.  Modeling precision treatment of breast cancer , 2013, Genome Biology.

[62]  Ron Edgar,et al.  LifeMap Discovery™: The Embryonic Development, Stem Cells, and Regenerative Medicine Research Portal , 2013, PloS one.

[63]  M. Prasad,et al.  Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas , 2013, British Journal of Cancer.

[64]  J. Taube,et al.  Neural crest transcription factor Sox10 is preferentially expressed in triple-negative and metaplastic breast carcinomas. , 2013, Human pathology.

[65]  Michal Sheffer,et al.  Pathway-based personalized analysis of cancer , 2013, Proceedings of the National Academy of Sciences.

[66]  M. Bronner,et al.  A PHD12–Snail2 repressive complex epigenetically mediates neural crest epithelial-to-mesenchymal transition , 2012, The Journal of cell biology.

[67]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[68]  Wenjun Guo,et al.  Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State , 2012, Cell.

[69]  C. Perou,et al.  Defining the cellular precursors to human breast cancer , 2011, Proceedings of the National Academy of Sciences.

[70]  A. Xiao,et al.  Epigenetic regulation in neural crest development. , 2011, Birth defects research. Part A, Clinical and molecular teratology.

[71]  Paul A. Wiggins,et al.  Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state , 2011, Proceedings of the National Academy of Sciences.

[72]  E. Lander,et al.  Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. , 2011, Cell stem cell.

[73]  A. Ashworth,et al.  BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. , 2010, Cell stem cell.

[74]  Jason I. Herschkowitz,et al.  Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer , 2010, Breast Cancer Research.

[75]  S. Fox,et al.  Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers , 2009, Nature Medicine.

[76]  Paula D. Bos,et al.  Metastasis: from dissemination to organ-specific colonization , 2009, Nature Reviews Cancer.

[77]  Steve Horvath,et al.  WGCNA: an R package for weighted correlation network analysis , 2008, BMC Bioinformatics.

[78]  L. Chiriboga,et al.  Sox10: A Pan-Schwannian and Melanocytic Marker , 2008, The American journal of surgical pathology.

[79]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[80]  D. Easton,et al.  Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival , 2007, Breast Cancer Research.

[81]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[82]  M. Hendrix,et al.  Reprogramming metastatic melanoma cells to assume a neural crest cell-like phenotype in an embryonic microenvironment. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[83]  A. Feinberg,et al.  The epigenetic progenitor origin of human cancer , 2006, Nature Reviews Genetics.

[84]  S. Horvath,et al.  A General Framework for Weighted Gene Co-Expression Network Analysis , 2005, Statistical applications in genetics and molecular biology.

[85]  D. Newgreen,et al.  Sox10 overexpression induces neural crest‐like cells from all dorsoventral levels of the neural tube but inhibits differentiation , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[86]  David J. Anderson,et al.  SOX10 Maintains Multipotency and Inhibits Neuronal Differentiation of Neural Crest Stem Cells , 2003, Neuron.

[87]  I. Sekine,et al.  Expression of the ets-1 proto-oncogene in human thyroid tumor. , 1999, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[88]  W. Pavan,et al.  SOX10 mutation disrupts neural crest development in Dom Hirschsprung mouse model , 1998, Nature Genetics.

[89]  V. A. Triolo.  NINETEENTH CENTURY FOUNDATIONS OF CANCER RESEARCH ADVANCES IN TUMOR PATHOLOGY, NOMENCLATURE, AND THEORIES OF ONCOGENESIS. , 1965, Cancer research.

[90]  C. Waddington.  Cancer and the Theory of Organisers , 1935, Nature.