Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis
Menée à l'aide de lignées cellulaires, de modèles murins de tumeur mammaire ou pancréatique et de données du projet "The Cancer Genome Atlas" portant sur des patientes atteintes d'un cancer du sein, cette étude met en évidence un mécanisme par lequel le blocage intratumoral de la kinase MNK1 restreint l'adaptation métabolique de la tumeur et supprime les métastases hépatiques en réduisant la glycolyse et en augmentant la dépendance des cellules cancéreuses à la phosphorylation oxydative
Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)–eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited. Omics-based study and TCGA analyses reveal an unappreciated role of MNK1 in supporting tumor cell glycolysis and liver metastasis.
Science Advances , article en libre accès, 2023