Multifaceted activities of transcription factor eb in cancer onset and progression

Transcription factor EB (TFEB) represents an emerging player in cancer biology. Together with microphthalmia-associated transcription factor, transcription factor E3 and transcription factor EC, TFEB belongs to the microphthalmia family of bHLH-leucine zipper transcription factors that may be implicated in human melanomas, renal and pancreatic cancers. In particular, TFEB was originally described to be translocated in a juvenile subset of paediatric renal cell carcinoma, however, whole genome sequencing reported somatic mutations sporadically found in many different cancers. Besides its oncogenic activity, TFEB controls the autophagy-lysosomal pathway by recognizing a recurrent motif present in the promoter regions of a set of genes that participate in lysosome biogenesis, furthermore its dysregulation was found to have a crucial pathogenic role in different tumors by modulating the autophagy process. Other than to regulate cancer cell-autonomous responses, recent findings indicate that TFEB participates in the regulation of cellular functions of the tumor microenvironment. Here, we review the emerging role of TFEB in regulating cancer cell behaviour and choreographing tumor-microenvironment interaction. Recognizing TFEB as a hub of network of signals exchanged within the tumor between cancer and stroma cells provides a fresh perspective on the molecular principles of tumor self-organization, promising to unveil numerous new and potentially druggable vulnerabilities.