Developmental programs in childhood embryonal tumors

Speaker: Prof. Frank Westermann
Institution: Neuroblastoma Research Group, Head Division, Hopp-Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany.

Place: Jerónimo Forteza conference room, CIPF

Abstract: A prominent disparity between pediatric and adult cancers lies in the considerably lower mutational burden observed in pediatric malignancies. Unlike their adult counterparts, which often develop as a result of the gradual accumulation of genetic alterations over a longer lifespan, pediatric tumors originate in a relative short time from embryonic tissues that have undergone limited mutational changes. This lower genetic complexity is a distinctive feature of pediatric cancers and may point towards dependencies linked to fewer oncogenic drivers. Beyond mutational differences, the cell of origin plays a pivotal role in shaping the characteristics of pediatric cancers. Pediatric tumors (e.g., neuroblastoma, medulloblastoma, Ewing sarcoma) typically originate from fast-proliferating embryonic or fetal tissues, in contrast to adult cancers that predominantly arise from mature tissues with few cycling cells. Here, we studied the developing adrenal glands, sympathetic ganglia and neural crest tissue covering various developmental stages using single-nucleus RNA sequencing (snRNA-seq) to shed light on the normal development of sympathoadrenal cells in humans. Furthermore, childhood neuroblastomas were studied by snRNA-seq and their transcriptomes were compared to developing normal sympathoadrenal cells to gain insights into the developmental origins of neuroblastoma. In combination with functional genomic approaches, these transcriptome comparisons can be used to study the impact of oncogenes and tumor suppressor genes in neuroblastoma biology. Furthermore, we quantified somatic evolution of neuroblastomas by deep whole-genome sequencing, molecular clock analysis and population-genetic modeling in a comprehensive cohort covering all subtypes. We find that tumors across the entire clinical spectrum begin to develop via aberrant mitoses as early as in the first trimester of pregnancy. Neuroblastomas with favorable prognosis cease to evolve early, whereas aggressive neuroblastomas show prolonged evolution during which they acquire telomere maintenance mechanisms. In summary, understanding the developmental context and evolution of embryonal tumors is essential to identify unique vulnerabilities allowing for tailoring treatment approaches and optimizing outcomes.

PATROCINADO POR: