The long non-coding RNA SAMMSON is essential for uveal melanoma cell survival

Shanna Dewaele,Manuel Rodrigues,Peihua Zhao,Jasper Anckaert,Fariba Némati ,Eleonora Leucci,Rudy Van Coster,Justine Nuytens,Boél De Paepe ,Jean–Christophe Marine ,Jo Van Dorpe,Maxime Verschoore,Jo Vandesompele,Eric James De Bony,Louis Delhaye,Nurten Yigit,Sven Eyckerman,Aart G Jochemsen ,Katrien Vanderheyden,Joél Smet ,Didier Decaudin,Eveline Vanden Eynde,Jilke De Wilde,Pieter Mestdagh

doi:10.1038/s41388-021-02006-x

Abstract

Long non-coding RNAs (lncRNAs) can exhibit cell-type and cancer-type specific expression profiles, making them highly attractive as therapeutic targets. Pan-cancer RNA sequencing data revealed broad expression of the SAMMSON lncRNA in uveal melanoma (UM), the most common primary intraocular malignancy in adults. Currently, there are no effective treatments for UM patients with metastatic disease, resulting in a median survival time of 6–12 months. We aimed to investigate the therapeutic potential of SAMMSON inhibition in UM. Antisense oligonucleotide (ASO)-mediated SAMMSON inhibition impaired the growth and viability of a genetically diverse panel of uveal melanoma cell lines. These effects were accompanied by an induction of apoptosis and were recapitulated in two uveal melanoma patient derived xenograft (PDX) models through subcutaneous ASO delivery. SAMMSON pulldown revealed several candidate interaction partners, including various proteins involved in mitochondrial translation. Consequently, inhibition of SAMMSON impaired global, mitochondrial and cytosolic protein translation levels and mitochondrial function in uveal melanoma cells. The present study demonstrates that SAMMSON expression is essential for uveal melanoma cell survival. ASO-mediated silencing of SAMMSON may provide an effective treatment strategy to treat primary and metastatic uveal melanoma patients.

Highlights

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 5−7.4 cases per million annually [1,2,3]
No macro-metastatic lesions were observed in both patient derived xenograft (PDX) models, we investigated the presence of tumoral DNA in blood and various murine tissues resected from both PDX models [27]
The Long non-coding RNAs (lncRNAs) SAMMSON was discovered as a melanoma specific lncRNA [13], but several studies have shown occasional expression in gastric cancer (GC), hepatocellular carcinoma (HCC), glioblastoma (GBM) and papillary thyroid carcinoma (PTC) [30,31,32,33,34]

Summary

INTRODUCTION

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 5−7.4 cases per million annually [1,2,3]. SAMMSON expression was associated with a significant decrease in cell viability in 92.1 and detected in the conjunctival melanoma (CM) cell lines CRMM1 OMM1 (Supplemental Fig. 4B, p < 0.0001, one-way ANOVA). While the majority of genes expressed from chromosome 3, for SAMMSON inhibition affects protein synthesis and example Roundabout Guidance Receptor 1 (ROBO1) (Fig. 1F, p < mitochondrial function in UM 10−9, Mann-Whitney test), are significantly downregulated in To investigate the mechanism by which SAMMSON contributes to monosomy 3 UM tumors (Supplemental Fig. 2, 89% down- UM tumor cell survival, we studied SAMMSON interaction regulated genes (n = 581), 81% of those genes are significantly partners in UM cell lines. Mock NTC ASO ASO 11 (5 nM) ASO 11 (10 nM) ASO 11 (25 nM) ASO 11 (50 nM) ASO 11 (100 nM)

MRPL44 MRPL20

NTC ASO

Findings

DISCUSSION