노휘재 (Broad Institute of Harvard and MIT, 현 Pfizer)

한빛사논문, 상위피인용논문

조회856

Broad Institute of Harvard and MIT, 현 Pfizer

CV File 224 kb

Cancer Discov., MARCH 02 2021 | https://doi.org/10.1158/2159-8290.CD-19-1500 The lipogenic regulator SREBF2 induces Transferrin in circulating melanoma cells and suppresses ferroptosis.

Xin Hong¹, Whijae Roh², Ryan J. Sullivan^1,3, Keith H.K. Wong^4,5, Ben S. Wittner¹, Hongshan Guo¹, Taronish D. Dubash¹, Moshe Sade-Feldman^1,2, Benjamin Wesley¹, Elad Horwitz¹, Genevieve M. Boland^1,6, Dieuwke L. Marvin¹, Todd Bonesteel¹, Chenyue Lu¹, François Aguet², Risa Burr¹, Samuel S. Freeman², Laxmi Parida⁹, Katherine Calhoun^1,4, Michelle K. Jewett^1,4, Linda T. Nieman¹, Nir Hacohen^1,2, Anders M. Näär¹, David T. Ting^1,3, Mehmet Toner^4,5,6, Shannon L. Stott^1,3, Gad Getz^1,2,7, Shyamala Maheswaran^1,6, and Daniel A. Haber^1,3,8

¹Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts. ²Broad Institute of Harvard and MIT, Cambridge, Massachusetts. ³Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. ⁴Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. ⁵Shriners Hospitals for Children, Boston, Massachusetts. ⁶Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. ⁷Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. ⁸Howard Hughes Medical Institute, Bethesda, Maryland. 9IBM Research, Yorktown Heights, New York.

X. Hong and W. Roh contributed equally to this article.

Corresponding Authors: Daniel A. Haber

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.

논문정보

형식Research article
게재일2021년 03월 (BRIC 등록일 2022-08-19)
연구진국외 연구진
분야 의약학 > 유전 및 유전체의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2022-12-19)

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