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Series GSE156024 Query DataSets for GSE156024
Status Public on Apr 30, 2023
Title Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer [ATAC-seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Despite important advances in the treatment of breast cancer, the 5-year survival rate for patients with distant metastasis remains less than 30%. Metastasis is a complex, multi-step process beginning with local invasion and ending with the outgrowth of systemically disseminated cells into actively proliferating metastases that ultimately cause the destruction of vital organs. It is this last step that limits patient survival and, at the same time, remains the least understood mechanistically. Here, we focus on understanding determinants of metastatic outgrowth using metastatic effusion biopsies from stage IV breast cancer patients. By modelling metastatic outgrowth through xenograft transplantation, we show that tumour initiation potential of patient-derived metastatic breast cancer cells across breast cancer subtypes is strongly linked to high levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels are caused by the irreversible reprogramming to a mesenchymal state with concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to retain epithelial traits is tied to a global epigenetic program that limits the actions of EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide direct evidence that maintenance of epithelial identity is required for metastatic outgrowth while concomitant expression of mesenchymal markers enables plasticity. In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our data provide a framework for the intricate intercalation of mesenchymal and epithelial traits in metastatic growth.
 
Overall design Omni-ATAC-sequencing on EMT-sensitive (M) and EMT-resistant (E) HMLE-Twist1-ER single-cell clones with a doxycyclin-inducible ZEB1 (NM00128128) or GUS construct.
 
Contributor(s) Eichelberger L, Saini M, Moreno HD, Klein C, Bartsch JM, Falcone M, Reitberger M, Espinet E, Vogel V, Graf E, Schwarzmayr T, Strom T, Lehmann M, Königshoff M, Pfarr N, Würth R, Donato E, Haas S, Spaich S, Sütterlin M, Schneeweiss A, Weichert W, Schotta G, Trumpp A, Sprick MR, Scheel CH
Citation(s) 37257449
Submission date Aug 11, 2020
Last update date Aug 10, 2023
Contact name Massimo Saini
E-mail(s) massimo.saini@unibas.ch
Phone 0762311275
Organization name University of Basel
Department Department of Biomedicine
Lab Nicola Aceto's Lab
Street address Mattenstrasse 28
City Basel
State/province Basel Canton
ZIP/Postal code 4058
Country Switzerland
 
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (10)
GSM4720585 GS1004_M-GUS_1
GSM4720586 GS1005_M-ZEB1_1
GSM4720587 GS1006_E-GUS_1
Relations
BioProject PRJNA656489
SRA SRP277033

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE156024_RAW.tar 2.6 Gb (http)(custom) TAR (of BIGWIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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