TOWARDS IDENTIFYING ETMR-LIKE PROGENITOR POPULATIONS IN DICER<SUP> </SUP>MUTANT MOUSE EMBRYOS

Embryonal tumors with multilayered rosettes (ETMRs) are highly aggressive pediatric brain tumors with very limited treatment options, partly due to the lack of suitable in vivo models. Our group has generated a mouse model in which Dicer is conditionally deleted in early telencephalic progenitors, leading to the formation of hyperproliferative rosettes resembling human ETMRs. To further characterize this model and assess whether it captures stem-like features of human ETMRs, we performed single-cell RNA sequencing on embryonic brains from wild-type (WT) and mutant mice and compared these profiles with published human ETMR single-cell datasets. We find that ETMR tumors display transcriptional profiles characteristic of very early human neurodevelopment, showing greater similarity to normal fetal brain cells from early gestational stages than to later developmental periods. Our analyses of mutant mouse samples show that these also retain transcriptional programs characteristic of early developmental stages, failing to progress into mature lineages. At embryonic day 12 (E12), we identified progenitor subpopulations in the mutant cortex and septum with strong transcriptional resemblance to human ETMR stem-like cells. By embryonic day 17 (E17), these populations were no longer detected in the cortex, and only a small population persisted in the septum, displaying reduced expression of tumor-specific signatures. Integration with human ETMR single-cell data confirmed high transcriptional similarity of E12 mutant samples to ETMR tumors. Our findings demonstrate that this Dicer-deficient mouse model reproduces key molecular and cellular features of ETMRs and provides new insights into the developmental origins of this tumor type.