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| Status |
Public on May 25, 2024 |
| Title |
LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a genome-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 up-regulation of the sodium/calcium (Na+/Ca2+) exchanger SLC8A1. This signalling cascade promotes increased level 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. We also designed an LKB1-deficient prognostic gene signature of patient survival that may be predictive of response to this 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.
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| Overall design |
To gain insights into the mechanisms by which LKB1 restricts metastatic uveal melanoma cell growth, we profiled the transcriptomes of Ctl and LKB1-KO cells in biological replicates.
6 samples of total RNA with 3 cell lines control, 3 KO cell lines for LKB1
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| Contributor(s) |
Strub T, Bertolotto C |
| Citation missing |
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| Submission date |
May 25, 2023 |
| Last update date |
May 25, 2024 |
| Contact name |
Corine Bertolotto |
| E-mail(s) |
corine.bertolotto@univ-cotedazur.fr
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| Organization name |
C3M - U1065 INSERM - CENTRE MEDITERRANEEN DE MEDECINE MOLECULAIRE
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| Street address |
151 route Saint-Antoine de Ginestière
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| City |
Nice |
| ZIP/Postal code |
06204 |
| Country |
France |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA976301 |
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