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The Lipogenic Regulator SREBP2 Induces Transferrin in Circulating Melanoma Cells and Suppresses Ferroptosis

Authors :
Anders M. Näär
Benjamin Wesley
Keith H. K. Wong
Moshe Sade-Feldman
Elad Horwitz
Whijae Roh
Gad Getz
David T. Ting
Linda T. Nieman
Shyamala Maheswaran
Samuel S. Freeman
Daniel A. Haber
Genevieve M. Boland
Xin Hong
Taronish D. Dubash
Katherine Calhoun
Hongshan Guo
Dieuwke L. Marvin
Mehmet Toner
Ben S. Wittner
Nir Hacohen
Michelle K. Jewett
Shannon L. Stott
Chenyue Lu
Laxmi Parida
Todd Bonesteel
François Aguet
Ryan J. Sullivan
Risa Burr
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

Details

ISSN :
21598290 and 21598274
Volume :
11
Database :
OpenAIRE
Journal :
Cancer Discovery
Accession number :
edsair.doi.dedup.....20cb27ce45dbba32ac523cc112c81204