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Series GSE142767 Query DataSets for GSE142767
Status Public on Dec 31, 2019
Title Chemogenomic profiling of breast cancer patient-derived xenografts reveals targetable vulnerabilities for difficult-to-treat tumors
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Breast cancer is a heterogeneous collection of disease arising from the breast with distinct molecular and phenotypic features. Certain subsets of patients have tumors that are particularly difficult-to-treat, which include triple-negative breast cancer (TNBC), metastatic/recurrent disease and rare histological variants. To delineate the underlying biology and identify therapeutic candidates for these patients, a series of 37 breast cancer patient-derived xenografts (PDX) from both chemo-naïve and pre-treated specimens was generated from 81 transplant attempts. Whole-genome and transcriptome sequencing revealed marked fidelity of the molecular landscape for the majority of PDXs in comparison to parental tumors. Reverse-phase protein array analysis of PDXs further identified potential therapeutic targets. Metastatic potential varied between PDXs, where low-penetrance lung micrometastases was the most common pattern of dissemination and observed in 34.5% of models. Three PDXs recapitulated the metastatic localization seen in the corresponding patients, including two lines with high-frequency metastases to multiple vital organ systems, while another PDX displayed tropism to the skull-base. Chemosensitivity profiling was performed in vivo with standard-of-care agents (doxorubicin, cisplatin, gemcitabine or paclitaxel), where multi-drug chemoresistance was found in 60.0% of PDXs and 64.7% of responses were concordant with pre-engraftment responses observed in the patient. Consolidating chemogenomic data identified potentially actionable features in 97.2% of PDXs, and marked regressions were seen in vivo when a subset of these underwent proof-of-concept functional studies. This included FGFR inhibitor sensitivity in a FGFR1-amplified lobular carcinoma, mTOR inhibitor sensitivity in a recurrent neuroendocrine breast cancer with proteomic evidence of mTOR/PI3K activation, and platinum sensitivity in a TNBC with BRCA1 germline mutation predicted as benign. Together, this clinically-annotated PDX library with comprehensive molecular and phenotypic profiling serves as a resource for both discovery and validation preclinical studies on difficult-to-treat breast tumors.
Overall design RNA sequencing data from breast cancer pairs of primary tumors and PDXs.
Contributor(s) Savage P, Pacis A, Kuasne H, Liu L, Lai D, Wan A, Muñoz-Ramos V, Pilon V, Monast A, Zhao H, Souleimanova M, Dankner MG, Annis M, Aguilar-Mahecha A, Bertos NR, Asselah J, Bouganim N, Petrecca K, Siegel PM, Omeroglu A, Shah SP, Aparicio S, Basik M, Meterissian S, Park M
Citation(s) 32546838
Submission date Dec 30, 2019
Last update date Jul 21, 2020
Contact name Alain Pacis
Organization name Canadian Centre for Computational Genomics (C3G)
Street address 740 Dr Penfield Ave
City Montreal
State/province QC
ZIP/Postal code H3A 0G1
Country Canada
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (66)
GSM4239854 GCRC1784T
GSM4239855 GCRC1784X_chondroid
GSM4239856 GCRC1784X_ductal
BioProject PRJNA598222
SRA SRP239118

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
GSE142767_RAW.tar 13.2 Mb (http)(custom) TAR (of TXT)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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