MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma

Diogo Dias; Erica Oliveira; Román Martí-Díaz; Sarah Andrews; Ana Chocarro-Calvo; Alice Bellini; Laura Mosteo; Yurena Vivas García; Jagat Chauhan; Linxin Li; José Manuel García-Martinez; José Neptuno Rodriguez-López; Silvya Stuchi Maria-Engler; Colin Kenny; Javier Martínez-Useros; Custodia García-Jiménez; Luis Sanchez-del-Campo; Pakavarin Louphrasitthiphol; Colin R. Goding

doi:10.1016/j.celrep.2025.116499

Back

MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma

Journal article

Open access

Peer reviewed

MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma

Diogo Dias, Erica Oliveira, Román Martí-Díaz, Sarah Andrews, Ana Chocarro-Calvo, Alice Bellini, Laura Mosteo, Yurena Vivas García, Jagat Chauhan, Linxin Li, …

Cell reports (Cambridge), Vol.44(12), 116499

11/21/2025

DOI: 10.1016/j.celrep.2025.116499

PMCID: PMC12828906

PMID: 41275493

Files and links (1)

url

https://doi.org/10.1016/j.celrep.2025.116499View

Published (Version of record) Open Access

Abstract

Cells can contain multiple related transcription factors targeting the same sequences, leading to potential regulatory cooperativity, redundancy, competition, or temporally regulated factor exchange. Yet, the differential biological functions of co-targeting transcription factors are poorly understood. In melanoma, three highly related transcription factors are co-expressed: the mammalian target of rapamycin complex 1 (mTORC1)-regulated TFEB and TFE3 (both key effectors of a wide range of metabolic and microenvironmental cues assumed to perform similar functions) and the microphthalmia-associated transcription factor (MITF), which controls melanoma phenotypic identity. Here, we reveal the functional specialization of MITF, TFE3, and TFEB and their impact on melanoma progression. Notably, although all bind the same sequences, each regulates different and frequently opposing gene expression programs to coordinate differentiation, metabolism, and protein synthesis and qualitatively and quantitatively impacts tumor immune infiltration. The results uncover a hierarchical cascade whereby microenvironmental stresses, including glucose limitation, lead MITF, TFEB, and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer. [Display omitted] •MITF promotes mTORC1 activity in melanoma•Low glucose suppresses MITF and then TFEB to leave TFE3 to promote survival•MITF, TFEB, and TFE3 bind the same targets but regulate distinct gene expression programs•The MITF family differentially regulates tumor immune cell infiltration Dias et al. reveal that in melanoma, the transcription factors MITF, TFE3, and TFEB share common binding sites but impose distinct transcriptional programs. Stresses promoting an MITF-to-TFEB-to-TFE3 switch will lead cells to suppress proliferation, reprogram metabolism, and impact tumor immune cell infiltration quantitatively and qualitatively.

melanoma

melanoma gene regulation

MITF

TFE3

TFEB

tumor immune infiltration

Details

Title: Subtitle: MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma
Creators: Diogo Dias - University of Oxford
Erica Oliveira - University of Oxford
Román Martí-Díaz - Instituto Murciano de Investigación Biosanitaria
Sarah Andrews - University of Oxford
Ana Chocarro-Calvo - Universidad Rey Juan Carlos
Alice Bellini - University of Oxford
Laura Mosteo - University of Oxford
Yurena Vivas García - University of Oxford
Jagat Chauhan - University of Oxford
Linxin Li - University of Oxford
José Manuel García-Martinez - Universidad Rey Juan Carlos
José Neptuno Rodriguez-López - Instituto Murciano de Investigación Biosanitaria
Silvya Stuchi Maria-Engler - Universidade de São Paulo
Colin Kenny - University of Iowa
Javier Martínez-Useros - Universidad Rey Juan Carlos
Custodia García-Jiménez - Universidad Rey Juan Carlos
Luis Sanchez-del-Campo - Instituto Murciano de Investigación Biosanitaria
Pakavarin Louphrasitthiphol - University of Oxford
Colin R. Goding - University of Oxford
Resource Type: Journal article
Publication Details: Cell reports (Cambridge), Vol.44(12), 116499
DOI: 10.1016/j.celrep.2025.116499
PMID: 41275493
PMCID: PMC12828906
NLM abbreviation: Cell Rep
ISSN: 2211-1247
eISSN: 2211-1247
Publisher: Elsevier Inc
Grant note: Ministerio de Ciencia, Innovacion y Universidades (MICIU): PID2023-149281OB-100 FEDERFundacio: Seneca, 21407/FPI/20 Agencia Estatal de Investigacio: MCIN/AEI/10.13039/501100011033 PID2023-151128OB-100, PID2019-10487RB-100, PID2021-127645OA-100 Comunidad de Madrid: PEJ-2021-AI/BMD-22973, PEJ-2021-TL/BMD-21515, P2022/BMD-7212
Ministerio de Ciencia, Innovacion y Universidades (MICIU) (project PID2023-149281OB-100 and FEDER, UE) , and Fundacion Seneca-Agencia de Ciencia y Tecnolog & imath;a de la Region de Murcia (FSRM/10.13039/100007801 (22544/PI/24, Spain) (J.N.R.-L.) ; Agencia Estatal de Investigacion: MCIN/AEI/10.13039/501100011033 PID2023-151128OB-100 and PID2019-10487RB-100 (C. G.-J.) and PID2021-127645OA-100 (A.C.-C.) ; Comunidad de Madrid: PEJ-2021-AI/BMD-22973 and PEJ-2021-TL/BMD-21515 and PRECICOLON-CM, P2022/BMD-7212 (C.G.-J.) ; and Fundacion Seneca, Region de Murcia (Spain) (21407/FPI/20) (R.M.-D.) .
Language: English
Date published: 11/21/2025
Academic Unit: Anatomy and Cell Biology; Surgery
Record Identifier: 9985035038202771

Metrics

5 Record Views

See more details