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LADON, a Natural Antisense Transcript of NODAL, Promotes Tumour Progression and Metastasis in Melanoma
Annie Dutriaux1, Serena Diazzi1, Chiara Bresesti1
1Institut Jacques Monod, Université Paris Cité, CNRS, F-75013 Paris, France.
Abstract:
The TGFβ family member NODAL, repeatedly required during embryonic development, has also been associated with tumour progression. Our aim was to clarify the controversy surrounding its involvement in melanoma tumour progression. We found that the deletion of the NODAL exon 2 in a metastatic melanoma cell line impairs its ability to form tumours and colonize distant tissues. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We show that LADON expression is specifically activated in metastatic melanoma cell lines, that its transcript is packaged in exosomes secreted by melanoma cells, and that, via its differential impact on the expression of oncogenes and tumour suppressors, it promotes the mesenchymal to amoeboid transition that is critical for melanoma cell invasiveness. LADON is, therefore, a new player in the regulatory network governing tumour progression in melanoma and possibly in other types of cancer.
Insights
A novel antisense transcript, LADON, derived from the NODAL gene, drives melanoma metastasis. Its exosomal packaging and role in promoting cell invasiveness highlight its significance in cancer progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Developmental Biology
Background:
- The TGFβ family member NODAL is crucial for embryonic development and has been implicated in tumor progression.
- Its specific role in melanoma progression remains controversial.
Purpose of the Study:
- To investigate the role of NODAL in melanoma tumor progression.
- To clarify the controversy surrounding NODAL's involvement in melanoma metastasis.
Main Methods:
- Utilized a metastatic melanoma cell line with a deletion in NODAL exon 2.
- Analyzed the expression of NODAL and its natural antisense transcript, LADON.
- Investigated LADON's presence in exosomes and its impact on gene expression and cell transition.
Main Results:
- Deletion of NODAL exon 2 impaired tumor formation and metastasis, but this was due to a defect in LADON expression, not NODAL absence.
- LADON expression is specifically activated in metastatic melanoma cell lines.
- LADON transcripts are packaged in exosomes and promote the mesenchymal to amoeboid transition, enhancing melanoma cell invasiveness.
Conclusions:
- LADON, a natural antisense transcript of NODAL, is a key driver of melanoma cell invasiveness and metastasis.
- LADON acts via exosomal packaging and modulation of oncogenes and tumor suppressors.
- LADON represents a novel regulatory factor in melanoma progression and potentially other cancers.
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