Circular DNA-driven cancer genome remodeling

ended

Recent reports describe the highly unexpected observation that cancer cells have the intrinsic ability to create and chromosomally re-incorporate extrachromosomal circular DNAs. We could show that these genomic phenomena are more frequent than expected in primary human neuroblastomas, a common childhood tumor, suggesting that DNA circularization represents a major driver of neuroblastoma genome remodeling. We aim with CancerCirculome to uncover new principles of pediatric cancer genome remodeling through an intensified study of the underlying mechanisms and functional consequences of extrachromosomal DNA circularization and chromosomal re-integration. Our long-term goal is to exploit these cancer cell-specific traits to improve cancer therapy, diagnosis and/or clinical risk stratification. Our work program will develop and establish new single-cell CRISPR-based methodologies with the aim to reveal molecular factors contributing to circular DNA generation. Furthermore, we will genetically engineer circular DNAs in human cells, assess their functional impact on cancer cell fitness and track their presence and chromosomal integration during therapy on a single-cell level. This aims to uncover the oncogenic functions of circular DNA and reveal the determinants of their chromosomal re-integration. The principles uncovered in CancerCirculome will be dissected to identify novel diagnostic and predictive markers for clinical application to improve personalized diagnosis, risk assessment and treatment of neuroblastoma, as our test case pediatric tumor. The work outlined in CancerCirculome promises to provide key insights into a fundamental biological and clinical problem and stongly impact the understanding of childhood solid tumors. CancerCirculome addresses fundamental questions about how cancer cells could arise and evolve at the roots of clonal evolution in tumors and at the mechanistic level of cellular genetics.