RARE-06. DISSECTING CELLULAR DIFFERENTIATION HETEROGENEITY IN CHOROID PLEXUS CARCINOMA PATHOGENESIS

Abstract Choroid plexus (CP) neoplasms are rare, predominantly pediatric, brain tumors ranging from benign CP papilloma to aggressive carcinoma (CPC) associated with poor survival. Survivors often experience devastating side effects current treatment strategies. There is an urgent need for safer, more effective therapies CPC. A subset of human CPC exhibits abnormal NOTCH activity, whereas mutations tumor suppressor gene TP53 detected in >50% and increased genetic instability worse prognosis. one hallmark Li-Fraumeni syndrome (LFS), a rare disorder germline mutations. Human also frequently display aberrant expression transcriptional regulators roof plate/CP differentiation, including LIM homeodomain transcription factors LMX1A, SRY-Box Transcription Factor 2 (SOX2). To investigate the role regulation tumorigenesis, animal models were developed driven by molecular defects commonly found humans. Accordingly, sustained Sonic Hedgehog (SHH) activation or combined deletion Rb1 Trp53 suppressors led malignant characteristics NOTCH-driven arose monociliated plate progenitors exhibited levels Lmx1a, Lmx1b, Sox2. In contrast, their was significantly reduced, while OTX2 markedly Rb1/Trp53-deficient Consistently, single-cell transcriptomics data show proliferative Otx2+ bulk small Lmx1a+/Sox2+ population Importantly, Sox2 Lmx1a+ blocked reduced Lmx1a/b expression. Thus, LMX1A SOX2 marks tumor-initiating cells, labels differentiated cells Together, our studies revealed intra- inter-tumoral heterogeneity distinct oncogenic signals. Knowledge cellular basis development may facilitate innovative diagnostic therapeutic strategies