Metabolic adaptations in melanoma brain metastasis

ABSTRACT Melanoma brain metastasis (MBM) is a deadly, poorly understood consequence of melanoma for which patients need improved treatment options. In integrating proteomics and transcriptomics data from independent patient cohorts, CNDP1 was identified as a commonly upregulated gene in MBM. CNDP1, or carnosine

dipeptidase-1, cleaves carnosine into its component amino acids L-histidine and ß-alanine. Carnosine is abundant in muscle, liver, and in the brain, where it exerts neuroprotective effects5. While carnosine itself is thought to exert anti-tumorigenic effects, the role of CNDP1 in cancer remains vastly unknown.

To probe the functional role of CNDP1 in MBM, we assessed the effects of CNDP1 depletion in MBM in vitro and in vivo. Constitutive CNDP1 silencing reduced melanoma cells’ ability to colonize the brain parenchyma, and inducible suppression impaired growth of established MBMs in preclinical mouse models. Mechanistically,

our preliminary studies suggest that, in addition to carnosine cleavage, CNDP1 may regulate cellular amino acid pools, aminoacyl-tRNA availability and protein translation, particularly of mitochondrial proteins. Our findings suggest the possibility that higher CNDP1 levels allow melanoma cells to withstand high carnosine levels and

oxidative stress during brain metastasis. This proposal aims to: 1) solidify the value and specificity of CNDP1 as a novel MBM target, using preclinical models and genetic and pharmacological approaches, and 2) dissect its mechanism(s) of action.