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Series GSE157743 Query DataSets for GSE157743
Status Public on Nov 13, 2020
Title The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis [single cell RNA-Seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Circulating tumor cells (CTCs) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastatic outgrowth. Here we show that CTCs from patients with BRAF-mutant melanoma coordinately upregulate both lipogenesis and iron homeostasis pathways. In clonally-derived cultures of melanoma CTCs these pathways are correlated with both intrinsic and acquired resistance to BRAF inhibitors. The lipogenesis regulator SREBF2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species (ROS) and lipid peroxidation, and conferring resistance to both BRAF inhibitors and inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic anti-oxidants Ferrostatin-1 and Vitamin E. In a cohort of patient-derived melanoma CTCs, single cell RNA-seq identifies a subset with high lipogenic, iron metabolic and proliferative signatures, which are correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBF2-driven iron homeostatic pathways contribute to cancer progression, drug resistance and metastasis.
 
Overall design We undertook single cell RNA-Seq of individually picked melanoma CTCs following microfluidic enrichment from primary blood specimens (PMID: 23552373, PMID: 24577360). We picked 76 individual CTCs freshly isolated from 22 melanoma patients and validated them to be melanoma cells by their expression of melanoma lineage markers (PMID: 29453278). We also picked and performed single cell RNA-Seq on 20 single CTCs that had been incubated in culture medium for 4-8 weeks, a condition in which only viable CTCs persist, but before they initiate in vitro proliferation. We also performed single cell RNA-Seq on six individually selected leukocytes from a healthy donor.
 
Contributor(s) Hong X, Roh W, Sullivan RJ, Wong KH, Wittner BS, Guo H, Dubash TD, Sade-Feldman M, Wesley BK, Horwitz E, Boland GM, Marvin DL, Bonesteel T, Lu C, Aguet F, Burr R, Freeman SS, Parida L, Calhoun K, Jewett MK, Nieman LT, Hacohen N, Naar AM, Ting DT, Toner M, Stott SL, Getz G, Maheswaran S, Haber DA
Citation(s) 33203734
Submission date Sep 09, 2020
Last update date Nov 23, 2020
Contact name Ben S. Wittner
E-mail(s) wittner.ben@mgh.harvard.edu
Organization name Massachusetts General Hospital
Department Center for Cancer Research
Lab Lawrence
Street address 149 13th Street
City Boston
State/province MA
ZIP/Postal code 02129
Country USA
 
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (102)
GSM4774351 Mel167_1 scRNA-seq
GSM4774352 Mel167_2 scRNA-seq
GSM4774353 Mel182_L1_3 scRNA-seq
This SubSeries is part of SuperSeries:
GSE157745 The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis
Relations
BioProject PRJNA662604
SRA SRP281893

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Supplementary file Size Download File type/resource
GSE157743_TPM.single_cell_RNA_Seq.csv.gz 2.2 Mb (ftp)(http) CSV
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Raw data are available in SRA
Processed data are available on Series record

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