Abstract
Purpose 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.
Experimental Design The impact of antisense oligonucleotide (ASO)-mediated SAMMSON inhibition was evaluated in a panel of UM cell lines and patient derived xenograft (PDX) models. Cell proliferation and apoptosis were quantified in vitro and in vivo and complemented with molecular profiles established through RNA-sequencing. SAMMSON interaction partners were identified using ChIRP-MS.
Results 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 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 protein translation levels and mitochondrial function in uveal melanoma cells.
Conclusion 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Additional information Financial support This work was supported by a Foundation Against Cancer grant (Stichting tegen Kanker), a Standup Against Cancer grant (Kom op tegen Kanker), a Ghent University Industrial Research Fund (IOF), a Ghent University GOA research grant and Fund for Scientific Research Flanders (FWO Vlaanderen). E.L. is the recipient of the Melanoma Research Alliance (MRA) Amanda and Jonathan Eilian young investigator award. S.D., L.D. and J.D.W. are recipients of a grant from the Fund of Scientific Research Flanders (FWO Vlaanderen).
Disclosure of Potential Conflicts of Interest, No potential conflicts of interest were disclosed.
Statement of translational relevance Despite localized treatment, 50% of uveal melanoma (UM) patients develop metastasis. For these patients, currently no effective treatments are available, resulting in a median survival time of less than 1 year. We demonstrate that the melanoma specific lncRNA SAMMSON is consistently expressed in UM tumors and that ASO-mediated SAMMSON knockdown abrogates cell viability and induces apoptosis of UM cells derived from both primary and metastatic UM tumors, independent of their genetic background. Furthermore, subcutaneous injection of a SAMMSON ASO in different uveal melanoma PDX models significantly impairs in vivo tumor growth. Together, our findings indicate that SAMMSON is an attractive therapeutic target in UM and that ASO-mediated SAMMSON targeting in vivo elicits therapeutic effects in PDX models.