Back to Search
Start Over
The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis
- Source :
- Cancer Discov
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Circulating tumor cells (CTC) are shed by cancer into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastasis. We show that single CTCs from patients with melanoma coordinately upregulate lipogenesis and iron homeostasis pathways. These are correlated with both intrinsic and acquired resistance to BRAF inhibitors across clonal cultures of BRAF-mutant CTCs. The lipogenesis regulator SREBP2 directly induces transcription of the iron carrier Transferrin (TF), reducing intracellular iron pools, reactive oxygen species, and lipid peroxidation, thereby conferring resistance to inducers of ferroptosis. Knockdown of endogenous TF impairs tumor formation by melanoma CTCs, and their tumorigenic defects are partially rescued by the lipophilic antioxidants ferrostatin-1 and vitamin E. In a prospective melanoma cohort, presence of CTCs with high lipogenic and iron metabolic RNA signatures is correlated with adverse clinical outcome, irrespective of treatment regimen. Thus, SREBP2-driven iron homeostatic pathways contribute to cancer progression, drug resistance, and metastasis. Significance: Through single-cell analysis of primary and cultured melanoma CTCs, we have uncovered intrinsic cancer cell heterogeneity within lipogenic and iron homeostatic pathways that modulates resistance to BRAF inhibitors and to ferroptosis inducers. Activation of these pathways within CTCs is correlated with adverse clinical outcome, pointing to therapeutic opportunities. This article is highlighted in the In This Issue feature, p. 521
- Subjects :
- 0301 basic medicine
medicine.disease_cause
Article
Metastasis
03 medical and health sciences
0302 clinical medicine
Circulating tumor cell
Downregulation and upregulation
Biomarkers, Tumor
medicine
Ferroptosis
Humans
Melanoma
Cells, Cultured
chemistry.chemical_classification
Gene knockdown
Chemistry
Lipogenesis
Transferrin
Neoplastic Cells, Circulating
medicine.disease
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Mutation
Cancer research
Disease Susceptibility
Single-Cell Analysis
Oxidative stress
Signal Transduction
Sterol Regulatory Element Binding Protein 2
Subjects
Details
- ISSN :
- 21598290 and 21598274
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Cancer Discovery
- Accession number :
- edsair.doi.dedup.....20cb27ce45dbba32ac523cc112c81204