Transposable elements in cancer cell drug response

Abstract

Transposable elements (TEs), which comprise nearly half of the human genome, have long been considered genomic parasites. However, emerging evidence reveals their dynamic roles in gene regulation, genome architecture, and cellular responses to environmental stimuli. This thesis investigates the influence of TEs on cancer cell response to cancer treatments, focusing on cisplatin in ovarian cancer and olaparib in triple-negative breast cancer (TNBC). Through multi-OMICs analyses of diverse conditions, this thesis demonstrates that both treatments modulate TE expression. Our results show that both treatments, cisplatin and olaparib, are associated with TE transcription, formation of chimeric transcripts, generation of double-stranded RNAs, and induction of L1 activity. These whole sets of TE-driven events impact protein coding gene expression, particularly genes associated with tumorigenesis and drug resistance. We also found that L1 activity along with TE repetitive nature are sources of structural variation. Together, these findings suggest that TEs contribute to tumor heterogeneity and therapeutic outcomes, positioning them as potential biomarkers and targets for combinatory anti-cancer therapies. While limited to in vitro models, this thesis underscores the translational relevance of TEs in oncology and advocates for their integration into future therapeutic strategies and clinical practices.