Journal article
Antagonistic roles for MITF and TFE3 in melanoma plasticity
Cell reports (Cambridge), Vol.44(4), 115474
03/25/2025
DOI: 10.1016/j.celrep.2025.115474
PMCID: PMC12376229
PMID: 40138313
Abstract
Melanoma cells can switch from a melanocytic and proliferative state to a mesenchymal and invasive state and back again. This plasticity drives intratumoral heterogeneity, progression, and therapeutic resistance. Microphthalmia-associated transcription factor (MITF) promotes the melanocytic/proliferative phenotype, but factors that drive the mesenchymal/invasive phenotype and the mechanisms that effect the switch between cell states are unclear. Here, we identify the MITF paralog, TFE3, and the non-canonical mTORC1 pathway as regulators of the mesenchymal state. We show that TFE3 expression drives the metastatic phenotype in melanoma cell lines and tumors. Deletion of TFE3 in MITF-low melanoma cell lines suppresses their ability to migrate and metastasize. Further, MITF suppresses the mesenchymal phenotype by directly or indirectly activating expression of FNIP1, FNIP2, and FLCN, which encode components of the non-canonical mTORC1 pathway, thereby promoting cytoplasmic retention and lysosome-mediated degradation of TFE3. These findings highlight a molecular pathway controlling melanoma plasticity and invasiveness.
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•MITF activates FNIP2 and additional components of non-canonical mTORC1 signaling•In MITF-high cells, mTORC1 signaling results in degradation of full-length TFE3•In MITF-low cells, full-length TFE3 occupies genes that regulate mesenchymal fate•In MITF-low cells, full-length TFE3 promotes distant colonization and metastasis
Chang et al. report that the acquisition of a mesenchymal phenotype in MITF-low melanoma cells is driven by TFE3. Melanocytic cells inhibit mesenchymal states through MITF-mediated activation of non-canonical mTORC1 signaling, leading to TFE3 degradation. Deletion of TFE3 in MITF-low melanoma cells significantly impairs cell invasion and distal lung colonization.
Details
- Title: Subtitle
- Antagonistic roles for MITF and TFE3 in melanoma plasticity
- Creators
- Jeremy Chang - University of IowaKatelyn R. Campbell-Hanson - University of IowaMarion Vanneste - University of IowaNicholas I. Bartschat - University of IowaRyan Nagel - University of IowaAsdis K. Arnadottir - University of IcelandHong Nhung Vu - University of IcelandCollin Montgomery - Department of Surgery, Carver College of Medicine, University of Iowa, Iowa City, IA, USAJulius Yevdash - University of IowaJiarui Jiang - University of IowaArdith Bhinu - University of IowaAnnika Helverson - University of IowaMichael D. Henry - University of IowaEiríkur Steingrímsson - University of IcelandRonald J. Weigel - University of IowaRobert A. Cornell - University of WashingtonColin Kenny - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.44(4), 115474
- DOI
- 10.1016/j.celrep.2025.115474
- PMID
- 40138313
- PMCID
- PMC12376229
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- National Institutes of Health: R01-AR062457 American Association for Anatomy (AAA)Holden Comprehensive Cancer Center (HCCC) at the University of Iowa: P30-CA086862 American Cancer Society: IRG-18-164-43 State of Iowa, Department of Health and Human Services: 588CC12 Icelandic Research Fund: 2410567
Initial experiments in this project were funded by a grant from the National Institutes of Health to R.A.C. (R01-AR062457) and from the American Association for Anatomy (AAA) to C.K. Subsequently, the project was supported by grants from the Holden Comprehensive Cancer Center (HCCC; P30-CA086862) at the University of Iowa. Additional support came from an institutional research grant from the American Cancer Society, administered through the HCCC, to C.K. (IRG-18-164-43) and from the State of Iowa, Department of Health and Human Services, to M.D.H. (grant #588CC12) and from the Icelandic Research Fund to E.S. (grant #2410567) . The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We gratefully acknowledge Dr. Christine Blaumueller of the Scientific Editing and Research Communication Core at the University of Iowa Carver College of Medicine for critical reading of the manuscript. We also acknowledge Mr. Christopher Franke and Dr. Nicholas Stone at the University of Iowa College of Medicine for bioinformatic support. We acknowledge lab management by Mr. Frank Radella at the University of Washington and Mr. Gregory Bonde at the University of Iowa. We also acknowledge experimental support from Mr. Dylan Friend and Mr. Isaac O'Toole at the University of Iowa.
- Language
- English
- Date published
- 03/25/2025
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Surgery; Radiation Oncology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984802412602771
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