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Series GSE157741 Query DataSets for GSE157741
Status Public on Nov 13, 2020
Title The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis [ChIP-Seq]
Organism Homo sapiens
Experiment type Genome binding/occupancy 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 To identify SREBF2-regulated genes mediating tumor-enhancing effects of SREBF2 expression, we undertook chromatin immunoprecipitation followed by Next Generation Sequencing (ChIP-Seq), defining direct SREBF2 transcriptional targets in cultured melanoma CTCs.
 
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 (3)
GSM4774318 s167FLAGrep1 ChIP-seq
GSM4774319 s167FLAGrep2 ChIP-seq
GSM4774320 s167In ChIP-seq
This SubSeries is part of SuperSeries:
GSE157745 The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis
Relations
BioProject PRJNA662602
SRA SRP281891

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Supplementary file Size Download File type/resource
GSE157741_RAW.tar 1.6 Mb (http)(custom) TAR (of NARROWPEAK)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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