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

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• Cells often have multiple transcription factors that bind to similar DNA sequences.
• The distinct biological roles of these co-targeting transcription factors are not well understood.
• In melanoma, MITF, TFE3, and TFEB are co-expressed and target similar sequences.

Purpose of the Study:

• To investigate the functional specialization of MITF, TFE3, and TFEB in melanoma.
• To understand their impact on melanoma progression, differentiation, metabolism, and immune infiltration.

Main Methods:

• Analysis of gene expression programs regulated by MITF, TFE3, and TFEB.
• Assessment of their impact on melanoma phenotypic transitions.
• Investigation of their roles under microenvironmental stresses like glucose limitation.

Main Results:

• MITF, TFE3, and TFEB, despite binding the same sequences, regulate distinct and often opposing gene expression programs.
• These factors coordinate cellular differentiation, metabolism, and protein synthesis.
• They also influence tumor immune infiltration both qualitatively and quantitatively.
• A hierarchical cascade driven by microenvironmental cues leads to distinct transcriptional programs.

Conclusions:

• MITF, TFE3, and TFEB exhibit functional specialization in melanoma, impacting tumor progression.
• These transcription factors play critical roles in coordinating cellular functions and phenotypic transitions.
• Understanding their distinct roles provides insights into melanoma heterogeneity and therapeutic strategies.