Proliferation of melanoma metastases in the absence of telomere maintenance mechanism
(2016) CSH Asia-Telomere & Telomerase — Location: Souzhou, China (5.September.2016)
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- Cutaneous melanoma is a very aggressive skin cancer with high propensity to metastasize. It is generally admitted that metastasis formation requires the acquisition of a telomere maintenance mechanism. As melanomas derive from melanocytes in which the expression of hTERT catalytic subunit of telomerase is repressed, reactivation of telomerase to acquire immortality often requires acquisition of one of the two recurrent and -believed to be- mutually exclusive C>T somatic mutations in hTERT promoter. C228T or C250T mutations, detected in about 80% of melanoma cell lines, create binding sites for GABP transcription factor. Here, we analyzed hTERT promoter mutations and telomere maintenance in a first series of lymph node metastases from ten melanoma patients and in cell lines freshly derived from these metastases. C228T and/or C250T mutations in hTERT promoter were found in eight cell lines that all expressed hTERT mRNA and were also detected in paired melanoma metastases. One cell line lacked expression of hTERT while another one failed to express hTR. Both telomerase-deficient cell lines were also negative for ALT features and displayed continuous telomere shortening in culture. Huge genomic instability was observed at late passages, characterized by sister chromatid/chromosome fusions, before massive cell death arose. Ectopic hTR overexpression in hTRneg cell line allowed continuous proliferation of the cells, showing that telomere shortening was the cause of cellular crisis. Intriguingly, one of these two telomeraseneg tumors was the most aggressive one from the series as, within less than one year, multiple visceral metastases appeared and patient died. Xenograft experiments with both telomerasepos and telomeraseneg cell lines in immuno-compromised mice are ongoing and preliminary results will be presented. We analyzed telomere maintenance mechanisms in additional metastases and primary melanoma cell lines and will discuss our first results. Our data provide evidence for the unexpected ability of melanoma tumors to form aggressive metastases in the absence of a telomere maintenance mechanism. These observations support the emerging notion brought up by R. Reddel’s group that telomere maintenance is not an absolute pre-requisite for metastasis formation and lethality in cancer patients and suggest that telomere-driven genomic instability may contribute to tumor aggressivity.
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Viceconte, N., Dheur, M.-S., Pierreux, C., van Baren, N., & Decottignies, A. (2016). Proliferation of melanoma metastases in the absence of telomere maintenance mechanism. CSH Asia-Telomere & Telomerase, Souzhou, China. https://hdl.handle.net/2078.5/179323