Bioinformatic analysis of transposable elements reactivation and Topoisomerase I poisoning-induced double strand breaks in human cancers

Genomic instability results from disruptions in key cellular processes like DNA replication, repair, transcription, chromatin remodeling, and cell cycle progression, leading to mutations and chromosomal abnormalities that contribute to tumorigenesis. Understanding its causes and effects is crucial for advancing cancer therapies. Features of genomic instability, like micronuclei and retrotransposon reactivation, are being used to improve the tumor microenvironment and support cancer immunotherapies by triggering immune responses and increasing lymphocyte infiltration in tumors. This PhD project investigates the mechanisms inducing genomic instability and how to harness it for cancer therapy. The first part examines how transposable elements (TEs) activate an innate immune response in small-cell lung cancer (SCLC). Transcriptomic data reveals that TEs are deregulated in SCLC, and that their expression is suppressed in these cancers due to epigenomic silencing. This repression likely prevents their immune-stimulatory effects, making TEs potential targets for immunotherapy. The second part explores the molecular basis of genomic instability induced by Top1 poisons, which stabilize Top1 cleavage complexes (Top1ccs). In colorectal cancer, Top1 poison treatment induces double-strand breaks (DSBs), especially in early-replicating regions of highly transcribed genes, leading to micronuclei formation and transcription-replication conflicts. Mutational analysis of metastatic colorectal cancer samples suggests that Top1 poisons are more likely to cause insertions/deletions in tumors, although further research is needed to assess their role in generating structural variations. In conclusion, my PhD project provides insights into cancer genome instability mechanisms, their implications for tumor progression, and how they can be exploited for cancer immunotherapy.