title: Extracellular metabolic energetics can promote cancer progression.
abstract: Colorectal cancer primarily metastasizes to the liver and globally kills over 600,000 people annually. By functionally screening 661 microRNAs (miRNAs) in parallel during liver colonization, we have identified miR-551a and miR-483 as robust endogenous suppressors of liver colonization and metastasis. These miRNAs convergently target creatine kinase, brain-type (CKB), which phosphorylates the metabolite creatine, to generate phosphocreatine. CKB is released into the extracellular space by metastatic cells encountering hepatic hypoxia and catalyzes production of phosphocreatine, which is imported through the SLC6A8 transporter and used to generate ATP—fueling metastatic survival. Combinatorial therapeutic viral delivery of miR-551a and miR-483-5p through single-dose adeno-associated viral (AAV) delivery significantly suppressed colon cancer metastasis, as did CKB inhibition with a small-molecule inhibitor. Importantly, human liver metastases express higher CKB and SLC6A8 levels and reduced miR-551a/miR-483 levels relative to primary tumors. We identify the extracellular space as an important compartment for malignant energetic catalysis and therapeutic targeting.
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Jia Min
authors.initials: JM
authors.lastname: Loo
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Scherl
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Fung Ying
authors.initials: FY
authors.lastname: Man
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Weinberg
authors.affiliation: Department of Surgery, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Medicine, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Leonard
authors.initials: L
authors.lastname: Saltz
authors.affiliation: Department of Surgery, Memorial-Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.affiliation: Laboratory of Systems Cancer Biology, Rockefeller University, New York, NY 10065, USA. Electronic address: stavazoie@mail.rockefeller.edu.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052276:Creatine Kinase, BB Form / Q000378:metabolism; D004734:Energy Metabolism; D005109:Extracellular Matrix; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism
chemical_list: C000595937:MIRN-551 microRNA, human; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C094770:SLC6A8 protein, human; D052276:Creatine Kinase, BB Form