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

Autor:	Hong X; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Roh W; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Sullivan RJ; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Wong KHK; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.; Shriners Hospitals for Children, Boston, Massachusetts., Wittner BS; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Guo H; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Dubash TD; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Sade-Feldman M; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Wesley B; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Horwitz E; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Boland GM; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Marvin DL; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Bonesteel T; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Lu C; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Aguet F; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Burr R; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Freeman SS; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Parida L; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Calhoun K; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Jewett MK; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Nieman LT; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Hacohen N; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts., Näär AM; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts., Ting DT; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Toner M; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.; Shriners Hospitals for Children, Boston, Massachusetts.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Stott SL; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Getz G; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.; Broad Institute of Harvard and MIT, Cambridge, Massachusetts.; Howard Hughes Medical Institute, Bethesda, Maryland., Maheswaran S; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Haber DA; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. dhaber@mgh.harvard.edu maheswaran@helix.mgh.harvard.edu.; Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.; IBM Research, Yorktown Heights, New York.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2021 Mar; Vol. 11 (3), pp. 678-695. Date of Electronic Publication: 2020 Nov 17.
DOI:	10.1158/2159-8290.CD-19-1500
Abstrakt:	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 . (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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