Blocking tumor-intrinsic MNK1 kinase restricts metabolic adaptation and diminishes liver metastasis.

Autor:	Preston SEJ; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Dahabieh MS; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Flores González RE; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Gonçalves C; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Richard VR; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Leibovitch M; MUHC Research Institute, McGill University Health Centre, Montréal, QC, Canada., Dakin E; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Papadopoulos T; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Lopez Naranjo C; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., McCallum PA; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Huang F; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Gagnon N; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Perrino S; MUHC Research Institute, McGill University Health Centre, Montréal, QC, Canada., Zahedi RP; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada.; Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, MB, Canada.; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.; CancerCare Manitoba, Winnipeg, MB, Canada., Borchers CH; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada.; Segal Cancer Proteomics Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada.; Department of Pathology, McGill University, Montréal, QC, Canada., Jones RG; Department of Metabolism and Nutritional Programming, Van Andel Institute, Grand Rapids, MI, USA., Brodt P; MUHC Research Institute, McGill University Health Centre, Montréal, QC, Canada.; Departments of Surgery, Oncology and Medicine, McGill University, Montréal, QC, Canada., Miller WH Jr; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada., Del Rincón SV; Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, QC, Canada.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2024 Sep 13; Vol. 10 (37), pp. eadi7673. Date of Electronic Publication: 2024 Sep 13.
DOI:	10.1126/sciadv.adi7673
Abstrakt:	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.
Databáze:	MEDLINE
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