title: Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism.
abstract: Activation of cellular stress response pathways to maintain metabolic homeostasis is emerging as a critical growth and survival mechanism in many cancers. The pathogenesis of pancreatic ductal adenocarcinoma (PDA) requires high levels of autophagy, a conserved self-degradative process. However, the regulatory circuits that activate autophagy and reprogram PDA cell metabolism are unknown. Here we show that autophagy induction in PDA occurs as part of a broader transcriptional program that coordinates activation of lysosome biogenesis and function, and nutrient scavenging, mediated by the MiT/TFE family of transcription factors. In human PDA cells, the MiT/TFE proteins--MITF, TFE3 and TFEB--are decoupled from regulatory mechanisms that control their cytoplasmic retention. Increased nuclear import in turn drives the expression of a coherent network of genes that induce high levels of lysosomal catabolic function essential for PDA growth. Unbiased global metabolite profiling reveals that MiT/TFE-dependent autophagy-lysosome activation is specifically required to maintain intracellular amino acid pools. These results identify the MiT/TFE proteins as master regulators of metabolic reprogramming in pancreatic cancer and demonstrate that transcriptional activation of clearance pathways converging on the lysosome is a novel hallmark of aggressive malignancy.
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Stoykova
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Brandon N
authors.initials: BN
authors.lastname: Nicolay
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Ross
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Boukhali
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Justine
authors.initials: J
authors.lastname: Lengrand
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Selig
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Ferrone
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.affiliation: Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haas
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D021581:Active Transport, Cell Nucleus; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004734:Energy Metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006706:Homeostasis; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000596:Amino Acids; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C069203:TFE3 protein, human; C064972:TFEB protein, human; D014157:Transcription Factors