Nora Fresmann

Adult stem cells are important for tissue turnover and regeneration. However, in most adult systems it remains elusive how stem cells assume different functional states and support spatially patterned tissue architecture. Here, we dissected the diversity of neural stem cells in the adult zebrafish brain, an organ that is characterized by pronounced zonation and high regenerative capacity. We combined single-cell transcriptomics of dissected brain regions with massively parallel lineage tracing and in vivo RNA metabolic labeling to analyze the regulation of neural stem cells in space and time. We detected a large diversity of neural stem cells, with some subtypes being restricted to a single brain region, while others were found globally across the brain. Global stem cell states are linked to neurogenic differentiation, with different states being involved in proliferative and non-proliferative differentiation. Our work reveals principles of adult stem cell organization and establishes a resource for the functional manipulation of neural stem cell subtypes.

The presence of supernumerary centrosomes is a hallmark of cancer and is frequently observed in aggressive tumors. Cancer cells with centrosome amplification achieve pseudo-bipolar spindles through specific coping mechanisms in order to survive. However, their distribution and prevalence in cancer remain largely unknown. Here, using the NCI60 panel of cancer cell lines, we show that the presence of coping strategies correlates with centrosome amplification, with the clustering of extra-centrosomes within the two spindle poles being the most widespread mechanism. Moreover, we report an association between centrosome clustering ability and the epithelial-to-mesenchymal transition (EMT) and observe that the induction of mesenchymal characteristics in breast cancer cells with centrosome amplification promotes clustering. Furthermore, we unveil hematological malignancies, which lack epithelial characteristics, as the most proficient in centrosome clustering. Finally, we show that acute lymphoblastic leukemia is particularly sensitive to targeting clustering through inhibition of the spindle assembly checkpoint. Our study reveals how centrosome clustering and EMT collaborate to promote carcinogenesis, suggesting new possibilities to treat tumors with low epithelial characteristics, in particular leukemias.

Abstract Neuroblastoma, a neural-crest-derived malignancy of the peripheral nervous system, is a devastating pediatric disease, characterized by high intra- and intertumoral heterogeneity. While expression of several tumor expression modules correlates with poor patient survival, the determinants of their emergence and plasticity remain elusive. Here, we systematically dissected neuroblastoma transcriptional heterogeneity and measured how tumor expression programs are determined by early developmental signaling versus local tumor environment. To achieve this, we combined single-cell transcriptomics with high-throughput lineage tracing and tumor cell transplantations in zebrafish models of high-risk neuroblastoma. We observed transcriptional programs determined by the cell of origin, including an ALK-activated state linked to poor disease prognosis in humans – in contrast to plastic states associated with physiological processes. Even lineage-determined tumor states can be reprogrammed upon exposure to a developmental signaling environment, indicating high plastic potential in vivo and a crucial role for the signals received in early tumorigenesis for tumor phenotype.