MiT/TFE Proteins Mediate Metabolic Reprogramming in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDA) is characterized by a hypoxic, nutrient-poor microenvironment and relies on scavenging pathways to obtain macromolecular substrates required for tumor growth. These pathways, autophagy and macropinocytosis, converge on the lysosome, where degradation and recycling of nutrient building blocks occurs. However, the mechanism by which autophagy is activated and whether autophagy and macropinocytosis are functionally integrated are unknown. Perera and colleagues found that, in addition to increased autophagosomes, PDA cells exhibited elevated lysosomal biogenesis and increased expression of an autophagy–lysosome gene program, suggesting that autophagy and lysosomal function may be coordinately regulated at the transcriptional level. Consistent with this idea, the MiT/TFE family of transcription factors, microphthalmia-associated transcription factor (MITF), transcription factor binding to IGHM enhancer 3 (TFE3), and transcription factor EB (TFEB), which regulate autophagosome and lysosome biogenesis under nutrient stress, were highly expressed in PDA cells. Knockdown of MiT/TFE proteins in PDA cells repressed the autophagy–lysosome gene signature, leading to defects in lysosome activity and impairments in both autophagy and macropinocytosis. PDA cells displayed constitutive MiT/TFE nuclear localization and activation independent of nutrient status and despite intact mTOR complex 1 (mTORC1) signaling, which normally induces cytoplasmic retention of MiT/TFE proteins. This escape from mTORC1-mediated inhibition was dependent on the nuclear import protein importin 8 (IPO8), which interacted with TFE3, was highly expressed in human PDA cells, and was required for MiT/TFE nuclear accumulation and stabilization in PDA cells. Global metabolite profiling revealed that elevated autophagosome–lysosome function in PDA cells was necessary to maintain intracellular amino acid levels and enable cell survival. In support of this finding, MiT/TFE depletion decreased the growth of PDA cell lines and suppressed xenograft tumor growth, whereas MITF overexpression enhanced tumor formation. These results identify MiT/TFE proteins as central regulators of metabolic reprogramming in PDA and define autophagy–lysosome activation as a hallmark and potential therapeutic target of PDA.

Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy–lysosome function drives pancreatic cancer metabolism. Nature 2015 Jul 13 [Epub ahead of print].

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