SOX2 commands LIM homeobox transcription factors in choroid plexus development and tumorigenesis.

Background: Choroid plexus (CP) tumors are rare brain neoplasms that mainly affect the pediatric population. Unlike benign CP papilloma (CPP), CP carcinoma (CPC) is an aggressive cancer with a dismal survival rate. Despite chromosome-wide rearrangements, drivers of most CP tumors remain elusive except recurrent alterations in TP53. Studies of signaling dysregulation 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 functions in the molecular signature of tumor cells were investigated.

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. 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.