Lactate-fueled hydride transfer metabolon drives breast cancer metastasis
Igelmann, S.;Jovanovic, P.;Bourdeau, V.;Curdy, N.;Zhan, L.;Palia, R.;Papadopoli, D.;Avizonis, D.;Paquet, M.;McLaughlan, S.;Nincic-Gajic, T.;Taylor, L.;Trempe, J.;Ursini-Siegel, J.;Ferbeyre, G.;Topisirovic, I.
Show abstract
Metabolic plasticity of cancer cells plays a major role in metastasis. Use of alternative carbon fuels (e.g., lactate) boosts metabolic plasticity, but the underlying mechanisms remain obscure. We show that lactate dehydrogenase B (LDHB) cooperates with the hydride ion transfer complex (HTC) comprised of pyruvate carboxylase (PC), malic enzyme (ME1) and malate dehydrogenase (MDH1) to form a metabolon that confers metabolic flexibility through lactate assimilation under physiological conditions. HTC/LDHB metabolon assembles in the aggressive breast cancer subtypes and reprograms nicotinamide adenine dinucleotide (NAD) metabolism to promote migration, invasion and escape from anoikis - thereby driving metastasis. Altogether, this work identifies a lactate-fueled metabolon that propels metastatic dissemination of breast cancer.
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