EMBO Molecular Medicine (Dec 2023)
LKB1‐SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition
- Sarah Proteau,
- Imène Krossa,
- Chrystel Husser,
- Maxime Guéguinou,
- Federica Sella,
- Karine Bille,
- Marie Irondelle,
- Mélanie Dalmasso,
- Thibault Barouillet,
- Yann Cheli,
- Céline Pisibon,
- Nicole Arrighi,
- Sacha Nahon‐Estève,
- Arnaud Martel,
- Lauris Gastaud,
- Sandra Lassalle,
- Olivier Mignen,
- Patrick Brest,
- Nathalie M Mazure,
- Frédéric Bost,
- Stéphanie Baillif,
- Solange Landreville,
- Simon Turcotte,
- Dan Hasson,
- Saul Carcamo,
- Christophe Vandier,
- Emily Bernstein,
- Laurent Yvan‐Charvet,
- Mitchell P Levesque,
- Robert Ballotti,
- Corine Bertolotto,
- Thomas Strub
Affiliations
- Sarah Proteau
- University Côte d'Azur Nice France
- Imène Krossa
- University Côte d'Azur Nice France
- Chrystel Husser
- University Côte d'Azur Nice France
- Maxime Guéguinou
- University of Tours Tours France
- Federica Sella
- Department of Dermatology, University Hospital Zurich University of Zurich Zurich Switzerland
- Karine Bille
- University Côte d'Azur Nice France
- Marie Irondelle
- University Côte d'Azur Nice France
- Mélanie Dalmasso
- University Côte d'Azur Nice France
- Thibault Barouillet
- Inserm, Hematometabolism and metainflammation, team 13, Mediterranean Centre for Molecular Medicine Nice France
- Yann Cheli
- University Côte d'Azur Nice France
- Céline Pisibon
- University Côte d'Azur Nice France
- Nicole Arrighi
- University Côte d'Azur Nice France
- Sacha Nahon‐Estève
- University Côte d'Azur Nice France
- Arnaud Martel
- University Côte d'Azur Nice France
- Lauris Gastaud
- Centre Antoine Lacassagne Nice France
- Sandra Lassalle
- University Côte d'Azur Nice France
- Olivier Mignen
- LBAI, UMR1227, Univ Brest, Inserm Brest France
- Patrick Brest
- University Côte d'Azur Nice France
- Nathalie M Mazure
- University Côte d'Azur Nice France
- Frédéric Bost
- University Côte d'Azur Nice France
- Stéphanie Baillif
- University Côte d'Azur Nice France
- Solange Landreville
- Département d'ophtalmologie et d'ORL‐CCF, Faculté de médecine Université Laval Quebec City QC Canada
- Simon Turcotte
- Cancer Axis Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal Montréal QC Canada
- Dan Hasson
- Department of Oncological Sciences, Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA
- Saul Carcamo
- Department of Oncological Sciences, Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA
- Christophe Vandier
- University of Tours Tours France
- Emily Bernstein
- Department of Oncological Sciences, Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York NY USA
- Laurent Yvan‐Charvet
- University Côte d'Azur Nice France
- Mitchell P Levesque
- Department of Dermatology, University Hospital Zurich University of Zurich Zurich Switzerland
- Robert Ballotti
- University Côte d'Azur Nice France
- Corine Bertolotto
- University Côte d'Azur Nice France
- Thomas Strub
- University Côte d'Azur Nice France
- DOI
- https://doi.org/10.15252/emmm.202317719
- Journal volume & issue
-
Vol. 15,
no. 12
pp. n/a – n/a
Abstract
Abstract Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome‐wide CRISPR‐Cas9 knockout screen, which revealed the LKB1‐SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria‐targeted antioxidant promotes enhanced cell death efficacy in LKB1‐ and SIK2‐negative uveal melanoma cells compared to control cells. Our study also identified an LKB1‐loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.
Keywords