Overactivation of SHH Signaling Induces a Cascade of Dedifferentiation and Oncogenesis in a New Mouse Model for Choroid Plexus Carcinoma

Abstract Choroid Plexus tumors constitute 10–20% of brain tumors in infancy. Among these, Choroid Plexus Carcinomas (CPC) are highly aggressive and result in poor survival. Details on tumor initiation and oncogenic events remain largely unknown, aside from a high prevalence of TP53 mutations and marked chromosomal instability. We generated hGFAP-cre::lsl-MYCN::lsl-Gli2(N)::Tp53 fl/fl mice with recombination activity from embryonic day 13.5 onwards in CNS cells, leading to MYCN and Gli2 activation as well as TP53 inactivation. 84% of the mice developed ventricular tumors within 18 days of life, resembling human CPCs in histology and marker expression. We performed histological and molecular characterization of the resulting tumors and treated tumor cells in vitro. We demonstrate that aberrant Sonic Hedgehog (SHH) signaling during embryonic Choroid Plexus (CP) development triggers a dedifferentiation cascade that reverts mature epithelium to a progenitor-like state. Spatial transcriptomic analysis identifies a distinct cellular hierarchy, where differentiated plexus cells shed their secretory identity to adopt malignant progenitor states. This transformation is accompanied by a transition from multiciliated epithelial cells expressing mature, secretory CP markers to highly proliferative, monociliated progenitors expressing SOX2. This malignant reprogramming activates embryonic developmental programs and induces a critical dependency on cell cycle and DNA repair pathways. Consequently, we identify that these tumor cells cultivated in vitro are vulnerable to ATR and CDK inhibition.