MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma
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.
Authors
- Silvya Stuchi Maria–Engler (ORCID: https://orcid.org/0000-0003-4771-6041)
- Colin R. Goding (ORCID: https://orcid.org/0000-0002-1614-3909)
- Román Martí-Díaz (ORCID: https://orcid.org/0000-0001-5792-7665)
- Jagat Chauhan (ORCID: https://orcid.org/0000-0003-4210-6260)
- Laura Mosteo (ORCID: https://orcid.org/0000-0002-4410-2370)
- Pakavarin Louphrasitthiphol
- S. D. Andrews (ORCID: https://orcid.org/0000-0002-1406-0982)
- Colin Kenny (ORCID: https://orcid.org/0000-0001-8926-4413)
- Yurena Vivas (ORCID: https://orcid.org/0000-0002-0230-4521)
- Érica A. Oliveira (ORCID: https://orcid.org/0000-0002-1624-4021)
- José Manuel García-Martínez (ORCID: https://orcid.org/0000-0002-6498-5174)
- Ana Chocarro‐Calvo (ORCID: https://orcid.org/0000-0003-1476-4848)
- Alice Bellini (ORCID: https://orcid.org/0000-0002-1347-6855)
- Custodia García‐Jiménez (ORCID: https://orcid.org/0000-0003-0146-4424)
- Diogo Dias (ORCID: https://orcid.org/0000-0003-4896-6720)
- Javier Martínez‐Useros (ORCID: https://orcid.org/0000-0001-9007-828X)
- Luis Sanchez-Del-Campo
- José Neptuno Rodrı́guez-López (ORCID: https://orcid.org/0000-0001-6863-1173)
- Linxin Li (ORCID: https://orcid.org/0000-0001-6858-9876)
Institutions
- University of Iowa (US)
- Universidade de São Paulo (BR)
- Universidad Rey Juan Carlos (ES)
- Ludwig Cancer Research (GB)
- Instituto Murciano de Investigación Biosanitaria (ES)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-11-22
- DOI
- https://doi.org/10.1016/j.celrep.2025.116499
- Citations
- 1
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.81