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Series GSE138329 Query DataSets for GSE138329
Status Public on Apr 30, 2023
Title Maintenance of epithelial traits and resistance to mesenchymal reprogramming promote proliferation in metastatic breast cancer
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Expression 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 and RNA-sequencing on EMT-sensitive (M1-M3) and EMT-resistant (E1-E3) HMLE-TWIST1-ER single-cell clones. RNA-seq on sorted EPCAM fractions of metastatic breast cancer cells from effusion biopsies from an ER+ (Patient 6, BPE22) and an ER- (Patient 1, BPE7) stage IV breast cancer patient.
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 Oct 02, 2019
Last update date Aug 10, 2023
Contact name Massimo Saini
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 (3)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
Samples (55)
GSM4105543 E2-TAMd1_ATAC-seq
GSM4105544 E1-TAMd1_ATAC-seq
GSM4105545 E3-TAMd1_ATAC-seq
BioProject PRJNA575519

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MINiML formatted family file(s) MINiMLHelp
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Supplementary file Size Download File type/resource
GSE138329_RAW.tar 3.8 Gb (http)(custom) TAR (of BIGWIG)
GSE138329_RNA-seq_HMLE_TWIST1_ER_all_counts.xlsx 3.4 Mb (ftp)(http) XLSX
GSE138329_RNA-seq_primary_breast_cancer_cells_raw_counts.xlsx 4.0 Mb (ftp)(http) XLSX
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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