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The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis.
- Source :
-
Cancer discovery [Cancer Discov] 2021 Mar; Vol. 11 (3), pp. 678-695. Date of Electronic Publication: 2020 Nov 17. - Publication Year :
- 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 .<br /> (©2020 American Association for Cancer Research.)
- Subjects :
- Biomarkers, Tumor
Cells, Cultured
Disease Susceptibility
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Melanoma pathology
Mutation
Neoplastic Cells, Circulating pathology
Signal Transduction
Single-Cell Analysis
Sterol Regulatory Element Binding Protein 2 metabolism
Ferroptosis genetics
Lipogenesis genetics
Melanoma genetics
Melanoma metabolism
Neoplastic Cells, Circulating metabolism
Sterol Regulatory Element Binding Protein 2 genetics
Transferrin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 11
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 33203734
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-19-1500