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Series GSE163360 Query DataSets for GSE163360
Status Public on Nov 02, 2022
Title JAK-STAT signaling in inflammatory breast cancer enables chemotherapy-resistant cell states [ChIP-seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. We previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation with stem cell-like features that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. We developed and characterized IBC cell lines resistant to paclitaxel and doxorubicin to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed genes associated with lineage identity and inflammation were enriched in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. We also investigated cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq. We identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, we showed that combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a new more effective therapeutic strategy in IBC.
 
Overall design ChIP-seq: Examination of pSTAT3 in SUM149 Parental or Paclitaxel resistant and FCIBC02 Parental, Paclitaxel or Doxorubicin resistant cell lines. Samples were either treated with vehicle, Paclitaxel, or Doxorubicin and sequenced without replicates.
Web link https://pubmed.ncbi.nlm.nih.gov/36409824/
 
Contributor(s) Stevens LE, Peluffo G, Qiu X, Trinh A, Temko D, Fassl A, Geck RC, Shu S, Kingston NL, Harper NW, Almendro V, Pyke AL, Egri SB, Papanastasiou M, Clement K, Walker S, Salas J, Park S, Frank DA, Meissner A, Jaffe JD, Sicinski P, Michor F, Toker A, Long H, Overmoyer BA, Polyak K, Li Z, Zhou N, Seehawer M, Jovanovic B
Citation(s) 36409824
Submission date Dec 16, 2020
Last update date Feb 01, 2023
Contact name Kornelia Polyak
E-mail(s) kornelia_polyak@dfci.harvard.edu
Phone 617-632-2106
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Polyak
Street address 450 Brookline Ave
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (14)
GSM4977484 FC-IBC02_Doxorubicin-Resistant_input
GSM4977485 FC-IBC02_Paclitaxel-Resistant_input
GSM4977486 FC-IBC02_Parental_input
This SubSeries is part of SuperSeries:
GSE163397 JAK-STAT signaling in inflammatory breast cancer enables chemotherapy-resistant cell states
Relations
BioProject PRJNA685804
SRA SRP298196

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

Supplementary file Size Download File type/resource
GSE163360_RAW.tar 5.4 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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