The carnosinase dipeptidase CNDP1 is a novel metabolic vulnerability in brain metastasis

Brain metastatic cells undergo metabolic adaptations, such as increased reliance on oxidative phosphorylation. Integrating proteomic and transcriptomic profiling of patient samples revealed a consistent upregulation of the carnosine dipeptidase-1 (CNDP1) in brain versus extracranial metastases. Carnosine is an abundant metabolite in brain and muscle, known to exert anti-proliferative effects on cancer cells. Here, we demonstrate that CNDP1 inhibition suppresses both the establishment and maintenance of melanoma brain metastasis while its ectopic expression is sufficient to confer brain metastatic potential to poorly metastatic cells. CNDP1 suppression results in activation of the Integrated Stress Response via Heme-Regulated Inhibitor Kinase and reprogrammed translation towards preferential expression of mitochondrial and survival transcripts. We further show that CNDP1 upregulation supports mitochondrial activity by limiting the levels of its substrate carnosine, a copper ionophore, thus protecting metastatic cells from carnosine-induced copper toxicity. Our studies reveal a novel metabolic adaptation during brain metastasis, which can be leveraged for therapeutic purposes.