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Series GSE210358 Query DataSets for GSE210358
Status Public on Sep 01, 2022
Title Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary In many cancers, treatment failure is linked to changes in tumor cell state or lineage, and often involves the reactivation of stem-like or developmental transcriptional programs. How this plasticity unfolds at a molecular level and whether it plays a causal role in drug resistance remains unclear. Here, we model the origin and dynamics of lineage plasticity in prostate cancer and its relationship to antiandrogen-based therapeutic resistance. In time course experiments utilizing genetically engineered mouse models and murine organoid cultures of prostate cancer, we find that plasticity initiates in an epithelial population defined by mixed luminal and basal lineage gene expression, and that it depends on elevated JAK and FGFR kinase activity. Organoid cultures from patients with late-stage castration-resistant disease harboring mixed-lineage cells reproduce the dependency we observe in mice, by upregulating luminal gene expression upon JAK and FGFR kinase inhibitor treatment. Single-cell analysis of human tumor samples confirms the presence of mixed lineage cells with elevated JAK/STAT and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.
 
Overall design Here, we model the origin and dynamics of lineage plasticity in prostate cancer and its relationship to antiandrogen-based therapeutic resistance. In time course experiments utilizing genetically engineered mouse models and murine organoid cultures of prostate cancer.
 
Contributor(s) Chan JM, Zaidi S, Karthaus W, Pe'er D, Sawyers CL
Citation(s) 35981096, 38645034
Submission date Aug 02, 2022
Last update date May 01, 2024
Contact name Dana Pe'er
E-mail(s) peerster@gmail.com
Organization name Memorial Sloan Kettering Cancer Center
Street address 417 E 68th St
City New York
State/province NY
ZIP/Postal code 10065
Country USA
 
Platforms (2)
GPL20301 Illumina HiSeq 4000 (Homo sapiens)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (49)
GSM6428946 Prostate organoid at 4 wks following cre mediated RB1 and TP53 deletion with enzalutamide exposure
GSM6428947 Prostate organoid at 8 wks following cre mediated RB1 and TP53 deletion with enzalutamide exposure
GSM6428948 Wild-type prostate organoid isolated from TP53 loxP/loxP and RB1 loxP/loxP mice with dihydrotestosterone exposure
Relations
BioProject PRJNA865372

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Supplementary file Size Download File type/resource
GSE210358_RAW.tar 33.5 Gb (http)(custom) TAR (of CSV, H5AD, TXT)
GSE210358_human_organoids.vst.expression.tissue_corrected.csv.gz 13.5 Mb (ftp)(http) CSV
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Processed data provided as supplementary file
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