Abstract B038: SOX2 promotes progenitor-like program choroid plexus development and tumorigenesis

Abstract Background. Tumors of the choroid plexus (CP) are a rare and heterogenous group of neoplasms that mostly occur in pediatric patients. CP tumors consist of choroid plexus papilloma (CPP, WHO grade 1), atypical choroid plexus papilloma (aCPP, WHO grade 2), and choroid plexus carcinoma (CPC, WHO grade 3). CPPs are mostly treated by surgery alone with excellent prognosis; however, CPC is an aggressive brain cancer associated with poor outcome, whereas survivors often suffer from debilitating long-term treatment effects. Despite chromosome-wide alterations, drivers of most CP tumors remain elusive except recurrent alterations in TP53. Studies of transcriptional and epigenetic changes may bring biological understanding of these malignancies. Previous studies implicated NOTCH signaling in CP tumors; we developed mouse models of CP tumors driven by NOTCH activation and TRP53 loss, respectively. This work examined the role of the transcription factor SOX2 in CP development and tumorigenesis. Methods. Multi-omics approaches were used to characterize cellular heterogeneity in NOTCH-driven CP tumors. SOX2 expression and functions in the molecular signature of tumor cells were investigated using genetic models, mouse primary CP tumor cell and human CP tumor cell lines. Results. Single-cell transcriptomics and epigenetics methods identified diverse cell populations in tumors that resemble normal CP, such as epithelial and glial groups. Pseudo-time trajectory analysis indicated that NOTCH-driven CP tumor arises from bi-potential glial progenitors and retains a progenitor-like signature characterized by an enhanced SOX2 profile, whereas NOTCH inhibition reduces SOX2 expression in tumor cells. SOX2 inactivation attenuated progenitor-like features and blunted tumor growth. Integrative omics studies revealed SOX2 binding to genes expressed in progenitors in the rhombic lip, including LIM homeobox transcription factors LMX1A and LMX1B. Consistently, SOX2 maintains progenitor identity through regulating their expression in CP tumors and during development, whereas LMX1A and LMX1B support SOX2 functions in tumor cell proliferation. Furthermore, spatial transcriptomics revealed aberrant SOX2 and LMX1A expression in human CP tumors. Conclusions. SOX2-LMX1 signaling maintains progenitor identity in CP development and tumor formation. Citation Format: Haotian Zhao, Mahek Chaudry, Siya Patel. SOX2 promotes progenitor-like program choroid plexus development and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_2):Abstract nr B038.