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| Status |
Public on Aug 25, 2016 |
| Title |
HER2 expression identifies dynamic functional states within circulating breast cancer cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance.
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| Overall design |
Seventy-four single candidate CTCs from two representative ER+/HER2- patients (BRx-42 and BRx-82) and 14 triple negative patients were isolated via micromanipulation and subjected to single-cell RNA-sequencing. Thirteen candidate CTCs expressed PTPRC at a level higher than 10 reads-per-million, so were deemed potential White Blood Cells and therefore dropped from further consideration. Expression profiles of CTCs expressing ERBB2 at a level greater than 10 RPM were compared with those expressing ERBB2 at a level less than 10 RPM.
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| Contributor(s) |
Jordan NV, Wittner BS, Bardia A, Benes C, Ligorio M, Zheng Y, Yu M, Sundaresan T, Desai R, O’Keefe R, Ebright RY, Barber TA, Kapur R, Sgroi D, Ting DT, Ramaswamy S, Toner M, Haas W, Maheswaran S, Haber DA |
| Citation(s) |
27556950 |
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| Submission date |
Nov 24, 2015 |
| Last update date |
Jan 29, 2020 |
| Contact name |
Ben S. Wittner |
| E-mail(s) |
wittner.ben@mgh.harvard.edu
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| Organization name |
Massachusetts General Hospital
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| Department |
Center for Cancer Research
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| Lab |
Lawrence
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| Street address |
149 13th Street
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02129 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (74)
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| Relations |
| BioProject |
PRJNA304018 |
| SRA |
SRP066632 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE75367_annotation_file.txt.gz |
345.4 Kb |
(ftp)(http) |
TXT |
| GSE75367_readCounts.txt.gz |
859.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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