Extracellular Metabolic Energetics Can Promote Cancer Progression

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...

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Bibliographic Details
Published in:Cell 2015-01, Vol.160 (3), p.393-406
Main Authors: Loo, Jia Min, Scherl, Alexis, Nguyen, Alexander, Man, Fung Ying, Weinberg, Ethan, Zeng, Zhaoshi, Saltz, Leonard, Paty, Philip B., Tavazoie, Sohail F.
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Colorectal Neoplasms - genetics
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - pathology
Creatine Kinase, BB Form - metabolism
Energy Metabolism
Extracellular Matrix
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms - metabolism
Liver Neoplasms - secondary
Male
Mice
Mice, Inbred NOD
Mice, SCID
MicroRNAs - metabolism
Neoplasm Metastasis - genetics
Neoplasm Metastasis - pathology
Nerve Tissue Proteins - metabolism
Plasma Membrane Neurotransmitter Transport Proteins - metabolism
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Summary: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. [Display omitted] [Display omitted] •miR-551a and miR-483-5p suppress colon cancer metastasis by targeting CKB•CKB promote metastatic survival by modulating intra- and extracellular energetics•miRNAs and CKB can be therapeutically targeted by AAV and small molecule delivery The tumor microenvironment is a rich source of metabolic substrates that could be utilized by cancer cells. Colon cancer cells secrete a kinase that acts extracellularly to generate one such metabolite, phosphocreatinine, that directly fuels tumor growth and metastasis to the liver.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2014.12.018