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bioRxiv · 10.64898/2026.06.16.732576

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.
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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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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.. 2026-06-21. Lactate-fueled hydride transfer metabolon drives breast cancer metastasis. https://doi.org/10.64898/2026.06.16.732576

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