ID #607 Developmental determinants of male bias in group 3/4 medulloblastoma
Luca Bianchini, Ruijie Xu, David Filipovic, Patricia Benites Goncalves da Silva, Laura Sieber, Vuslat Akçay, Frederik Arnskötter, Piyush Joshi, Jana Nolle, Taha Soliman, Ran Tao, Alexandra Scheuing, Konstantin Okonechnikov, Alexander Atamian, Marc Zuckermann, Giorgia Quadrato, Paul Northcott, Lena KutscherAbstract
Boys have an overall increased incidence of several childhood cancers relative to girls, including Group 3/4 medulloblastoma (boy:girl>2:1). Although part of the bias can be attributed to X-linked genes, most cases cannot be explained by known genetic factors. As tumor initiation is believed to occur during fetal development, this sex bias likely reflects prenatal sex-specific developmental processes.
To elucidate the developmental basis of the Group 3/4 sex bias, we generated a sex-matched single-cell RNA-seq atlas comprising over 300,000 cells from male and female murine cerebellum across seven developmental timepoints. At E16, GC_UBC progenitors giving rise to Group 3/4 medulloblastoma reach peak abundance, and male cells were more abundant and more cycling. To validate these findings, we isolated E16 GC_UBC progenitors using a novel genetically engineered mouse model and performed single-cell Multiome analysis. This dataset revealed differentially accessible chromatin regions that indicated intrinsically higher susceptibility to transformation in male cells. To determine whether the sexual dimorphism of this progenitor arises from intrinsic or extrinsic factors, we used the Four Core Genotype mouse model, which decouples presence of gonads from sex chromosome complement. Although presence of XY contributed to the abundance phenotype, the predominant effect was driven by presence of male testes. To assess the relevance of these findings in human cells, we generated human cerebellar organoids from XX and XY transgenic iPSC lines modified to carry a reporter for the lineage of origin of Group 3/4 medulloblastoma. Following treatment with dihydrotestosterone (DHT), estrogen or vehicle control, DHT-treated organoids harbored more LMX1A+ progenitor cells. Single-cell RNA seq of isolated LMX1A+ cells revealed a more progenitor-like state in the DHT-treated condition.
Altogether, we found that male progenitor cells giving rise to Group 3/4 medulloblastoma were more abundant and proliferative, providing a plausible explanation for the sex bias of this aggressive tumor type.