posted on 2025-05-09, 09:30authored byJane Loong, Rachael Thompson, Callum Hall, Laura Doglio, Judith Pape, Tobias Plowman, George Kassiotis
BACKGROUND: Transcriptional activation of otherwise repressed retrotransposable elements (RTEs) is a hallmark of cancer, shaping tumour progression and immunogenicity by multifaceted, yet incompletely understood, mechanisms. METHODS: We used an extended pan-cancer transcriptome assembly to identify potential effects of RTEs on the genes within which they have integrated or those in proximity. These were subsequently verified in test cases by further analysis of transcriptional profiles in cancer patient data, and by in vitro studies involving restoration of gene activity, and proliferation and migration assays in cancer cell lines. RESULTS: We report that cancer-specific transcriptional activation of RTEs causes frequent reduction or loss of gene function. Exonisation and alternative splicing of RTEs creates non-functional RNA and protein isoforms and derepressed RTE promoter activity initiates antisense transcription, both at the expense of the canonical isoforms. Contrary to theoretical expectation, transcriptionally activated RTEs affect genes with established tumour-promoting functions, including the common essential RNGTT and the lung cancer-promoting CHRNA5 genes. Furthermore, the disruptive effect of RTE activation on adjacent tumour-promoting genes is associated with slower disease progression in clinical data, whereas experimental restoration of gene activity enhances tumour cell growth and invasiveness in vitro. CONCLUSIONS: These findings underscore the gene-disruptive potential of seemingly innocuous germline RTE integrations, unleashed only by their transcriptional utilisation in cancer. They further suggest that such metastable RTE integrations are co-opted as sensors of the epigenetic and transcriptional changes occurring during cellular transformation and as executors that disrupt the function of tumour-promoting genes.
Funding
Crick (Grant ID: CC2088, Grant title: Kassiotis CC2088)
European Research Council (Grant ID: 101018670 - RETROFIT, Grant title: ERC 101018670 - RETROFIT)