EMBO Molecular Medicine (Nov 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
- Imène Krossa
- University Côte d'Azur
- Chrystel Husser
- University Côte d'Azur
- Maxime Guéguinou
- University of Tours
- Federica Sella
- Department of Dermatology, University Hospital Zurich, University of Zurich
- Karine Bille
- University Côte d'Azur
- Marie Irondelle
- University Côte d'Azur
- Mélanie Dalmasso
- University Côte d'Azur
- Thibault Barouillet
- Inserm, Hematometabolism and metainflammation, team 13, Mediterranean Centre for Molecular Medicine
- Yann Cheli
- University Côte d'Azur
- Céline Pisibon
- University Côte d'Azur
- Nicole Arrighi
- University Côte d'Azur
- Sacha Nahon‐Estève
- University Côte d'Azur
- Arnaud Martel
- University Côte d'Azur
- Lauris Gastaud
- Centre Antoine Lacassagne
- Sandra Lassalle
- University Côte d'Azur
- Olivier Mignen
- LBAI, UMR1227, Univ Brest, Inserm
- Patrick Brest
- University Côte d'Azur
- Nathalie M Mazure
- University Côte d'Azur
- Frédéric Bost
- University Côte d'Azur
- Stéphanie Baillif
- University Côte d'Azur
- Solange Landreville
- Département d'ophtalmologie et d'ORL‐CCF, Faculté de médecine, Université Laval
- Simon Turcotte
- Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal
- Dan Hasson
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Saul Carcamo
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Christophe Vandier
- University of Tours
- Emily Bernstein
- Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Laurent Yvan‐Charvet
- University Côte d'Azur
- Mitchell P Levesque
- Department of Dermatology, University Hospital Zurich, University of Zurich
- Robert Ballotti
- University Côte d'Azur
- Corine Bertolotto
- University Côte d'Azur
- Thomas Strub
- University Côte d'Azur
- DOI
- https://doi.org/10.15252/emmm.202317719
- Journal volume & issue
-
Vol. 15,
no. 12
pp. 1 – 18
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
