Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer
© 2022. The Author(s)..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
NPJ breast cancer - 8(2022), 1 vom: 02. Mai, Seite 57 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Saunus, Jodi M [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 16.07.2022 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1038/s41523-022-00425-x |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM340300930 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM340300930 | ||
| 003 | DE-627 | ||
| 005 | 20231226004831.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41523-022-00425-x |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1134.xml |
| 035 | |a (DE-627)NLM340300930 | ||
| 035 | |a (NLM)35501337 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Saunus, Jodi M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Epigenome erosion and SOX10 drive neural crest phenotypic mimicry in triple-negative breast cancer |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 16.07.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a De Luca, Xavier M |e verfasserin |4 aut | |
| 700 | 1 | |a Northwood, Korinne |e verfasserin |4 aut | |
| 700 | 1 | |a Raghavendra, Ashwini |e verfasserin |4 aut | |
| 700 | 1 | |a Hasson, Alexander |e verfasserin |4 aut | |
| 700 | 1 | |a McCart Reed, Amy E |e verfasserin |4 aut | |
| 700 | 1 | |a Lim, Malcolm |e verfasserin |4 aut | |
| 700 | 1 | |a Lal, Samir |e verfasserin |4 aut | |
| 700 | 1 | |a Vargas, A Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Kutasovic, Jamie R |e verfasserin |4 aut | |
| 700 | 1 | |a Dalley, Andrew J |e verfasserin |4 aut | |
| 700 | 1 | |a Miranda, Mariska |e verfasserin |4 aut | |
| 700 | 1 | |a Kalaw, Emarene |e verfasserin |4 aut | |
| 700 | 1 | |a Kalita-de Croft, Priyakshi |e verfasserin |4 aut | |
| 700 | 1 | |a Gresshoff, Irma |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Ejeh, Fares |e verfasserin |4 aut | |
| 700 | 1 | |a Gee, Julia M W |e verfasserin |4 aut | |
| 700 | 1 | |a Ormandy, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Khanna, Kum Kum |e verfasserin |4 aut | |
| 700 | 1 | |a Beesley, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Chenevix-Trench, Georgia |e verfasserin |4 aut | |
| 700 | 1 | |a Green, Andrew R |e verfasserin |4 aut | |
| 700 | 1 | |a Rakha, Emad A |e verfasserin |4 aut | |
| 700 | 1 | |a Ellis, Ian O |e verfasserin |4 aut | |
| 700 | 1 | |a Nicolau, Dan V |c Jr |e verfasserin |4 aut | |
| 700 | 1 | |a Simpson, Peter T |e verfasserin |4 aut | |
| 700 | 1 | |a Lakhani, Sunil R |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t NPJ breast cancer |d 2015 |g 8(2022), 1 vom: 02. Mai, Seite 57 |w (DE-627)NLM256806586 |x 2374-4677 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2022 |g number:1 |g day:02 |g month:05 |g pages:57 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41523-022-00425-x |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2022 |e 1 |b 02 |c 05 |h 57 | ||