Extracellular Metabolic Energetics Can Promote Cancer Progression

Abstract

Summary Colorectal cancer primarily metastasizes to the liver and kills over 600,000 people annually. By functionally screening 661 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 extracellular 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 metastatic colonization, 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.

Distinctive properties of metastasis-initiating cells

“…The phosphocreatine is then imported into the MICs to serve as an ATP source for growth functions ( Fig. 4A; Loo et al 2015). In metastatic ovarian cells, fatty acids secreted from adipocytes are imported by FABP4 in MICs to colonize the intra-abdominal fat (Nieman et al 2011).…”

“…Therefore, dormancy-specific treatment strategies should be designed to target the dormant cells (Sosa et al 2014;Ghajar 2015). Furthermore, other MIC-associated features, such as metabolic reprogramming and activation of survival pathways, are additional candidates for developing new treatment options (Holohan et al 2013;Loo et al 2015).…”

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…Recently, it was demonstrated that metastatic colorectal cancer cells reprogram hepatocyte-derived metabolites to enable the successful colonization and formation of liver metastases (97). miR-551 and miR-483 were identified as suppressors of efficient colorectal cancer liver metastasis through their ability to inhibit the expression of creatinine kinase brain-type.…”

Hepatocellular carcinoma redirects to ketolysis for progression under nutrition deprivation stress

“…Two groups reported recently that a variety of cancer types consume acetate avidly to fuel cancer growth [4][5][6]. More recently, Loo et al [7] documented that metastatic colorectal cancer cells rely on extracellular metabolite creatine to facilitate metastasis and cancer progression. Moreover, in addition to early reports that established lactate recycling as a significant fuel source for cancer progression [8,9], a most recent study showed that accumulated lactate facilitates hypoxia signaling to stimulate cancer growth [10].…”