Abstract 3095: Notch-induced choroid plexus tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth

Abstract

Abstract Introduction: Choroid plexus tumors are rare intraventricular papillary neoplasms arising from choroid plexus (CP) epithelium. They occur most often in childhood and comprise 10-20% of all brain tumors in infants. Choroid plexus papilloma is a benign tumor, whereas choroid plexus carcinoma is malignant and most commonly found in pediatric population. Knowledge of the oncogenic processes in CP tumor formation will profoundly impact the development of new and molecular targeted therapies. Previous studies implicate Notch signaling in CP tumorigenesis. However, mechanisms underlying Notch-driven CP tumor formation remain unclear. Animal models of CP tumors have great potential to facilitate the discovery and development of molecular diagnostics and targeted therapies for these rare diseases. Methods and Results: We used the Rosa26-NICD1 strain which will constitutively express the intracellular domain of Notch 1 (NICD1) from the Rosa26 locus after Cre-mediated DNA recombination. The hindbrain CP targeted for NICD1 expression was significantly enlarged with well circumscribed, globular, cauliflower like masses. Histological analysis revealed that CP from NICD1-expressing mutant mice contained an abnormal growth in the 4th ventricle consistent with properties of choroid plexus tumor. Tumor cells exhibit enhanced proliferation transiently after birth: tumor cell proliferation was highest at birth, then gradually decreased and completely stopped at 2 weeks after birth. While CP tumor cells expressed early CP lineage markers such as Lmx1a and Otx2, they didn’t express Aquaporin 1 (AQP1), marker for differentiated CP epithelial cells, suggesting lack of terminal differentiation. We further showed that CP tumor arises during development as ectopic Lmx1a+ cells in CP and exhibit properties similar to those of CP epithelium progenitors. However, unlike progenitor cells, tumor cells fail to exit the cell cycle and differentiate into mature epithelial cells. We characterized changes in gene expression in tumor cells by quantitative RT-PCR. Surprisingly, we detected increased levels of Shh, Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in proliferating tumor cells. CP tumor cells cultured in serum-free conditions underwent rapid proliferation in the presence of Shh. Ultra-structural studies revealed lack of multi-ciliation differentiation in tumors cells, whereas the expression of Foxj1 and Midas, crucial regulators of cilia differentiation, was significantly downregulated. Conclusions: We developed a genetic model of CP tumor driven by Notch signaling activation. Notch 1-induced CP tumor arises during development from CP epithelial progenitors but lack terminal differentiation and multi-ciliation of mature CP epithelial cells. The proliferation of Notch 1-induced tumors is supported by Shh pathway, indicating Shh pathway as a therapeutic target for Notch-driven CP tumors. Citation Format: Haotian Zhao, Li Li, Katie Picotte. Notch-induced choroid plexus tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3095. doi:10.1158/1538-7445.AM2014-3095