| Project Detail |
The impact of chemotherapy on the blood of young cancer survivors Chemotherapy targets dividing cancer cells inhibiting their growth and proliferation. However, it also affects normal cells such as those of the haematopoietic system leading to bone marrow damage and increasing the risk for infection and bleeding. With the support of the Marie Sklodowska-Curie Actions programme, the CYNAMIS project aims to explore the impact of chemotherapy on the clonal dynamics of haematopoiesis, mitochondrial dysfunction, and genetic integrity. Researchers will employ single-cell multiomics techniques in young cancer survivors and analyse mitochondrial and nuclear DNA for mutations, methylation, and chromatin status. Project findings are expected to identify mechanisms of accelerated ageing and mitochondrial dysfunction, aiming to improve clinical outcomes in cancer patients. Chemotherapy can cause significant damage to healthy tissues, especially in the hematopoietic system. As a result, cancer survivors may experience bone marrow damage manifested as cytopenias, which increase the risk of infections and bleeding. Despite this, there has not been a thorough examination of these events, including the clonal dynamics of hematopoiesis after chemotherapy exposure, due to a lack of methodologies to perform lineage tracing in humans in vivo. To address this, I will study the effects of chemotherapy on the clonal dynamics of hematopoiesis, mitochondrial dysfunction and genetic integrity in young cancer survivors. I will analyze samples obtained before, during, and after treatment using emerging single-cell multi-omic approaches to effectively capture mitochondrial DNA (mtDNA) genetic variation for inferences of clonal dynamics and studies of mtDNA damage. By combining mtDNA-based clonal inferences with whole-genome sequencing (WGS)-based detection of somatic nuclear DNA mutations, I will provide deep phylogenies with scalable single-cell resolved clonal measurements of perturbed hematopoiesis following chemotherapy. Moreover, orthogonal analysis of DNA methylation and chromatin accessibility data will yield new molecular insights into chemotherapy-induced accelerated aging and mitochondrial dysfunction (a hallmark of aging). This project sets out to gain quantitative and fundamental insights into the long-term molecular defects of chemotherapy in young cancer survivors, potentially paving the way for new interventions to improve the quality of life of this emergent population. |
