An MITF- and mTOR-dependent FLCN pathway suppresses TFE3-driven metastasis in melanoma.

Autor:	Chang J; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Campbell-Hanson KR; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Vanneste M; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA., Yevdash J; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Bartschat NI; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Jiang J; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Bhinu A; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Helverson A; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America., Henry MD; Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA, United States.; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA., Steingrímsson E; Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Weigel RJ; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America.; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA., Cornell RA; Department of Oral Health Sciences, University of Washington, School of Dentistry, Seattle, WA, USA., Kenny C; Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA, United States of America.; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 12. Date of Electronic Publication: 2024 Jul 12.
DOI:	10.1101/2024.07.11.603140
Abstrakt:	Cancer cells have remarkable plasticity allowing them to acquire many biological states. Melanoma cells have the ability to switch from a proliferative melanocytic state to an invasive mesenchymal state and back again resulting in intratumoral heterogeneity. While microphthalmia-associated transcription factor (MITF) promotes the melanocytic phenotype, it is unclear what transcription factors drive the mesenchymal phenotype, and what mechanisms regulate the switch from the proliferative state to the mesenchymal state. We show that nuclear localization of the MITF paralog TFE3 correlates positively with metastatic potential in melanoma cell lines and tumors, and that deletion of TFE3 in MITF-low melanoma cell lines eliminates migration and metastatic ability. Further, we find that MITF suppresses the mesenchymal phenotype by activating expression of FNIP2 , which encodes a component of an mTORC1-stimulated pathway promoting cytoplasmic retention and lysosomal degradation of TFE3. These findings point to the mTOR pathway and TFE3 as key regulators of melanoma plasticity. Competing Interests: Declaration of Interests: All authors declare no competing interests.
Databáze:	MEDLINE
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