Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development

Abstract

Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC.

Breakthroughs in choroid plexus and CSF biology from the first European Choroid plexus Scientific Forum (ECSF)

“…Clinically, this research is particularly relevant in the context of ciliopathies, such as de novo mutations in FOXJ1 resulting in motile ciliopathy characterised by hydrocephalus and airways defects [ 47 , 48 ]. Disruption of normal ChP multiciliation also underlies some forms of ChP tumorigenesis [ 20 ]. Ciliopathies have far-reaching implications, with potential impacts on brain health and function.…”

Sequential emergence and contraction of epithelial subtypes in the prenatal human choroid plexus revealed by a stem cell model

“…See Supplementary Information for detailed protocol information. dCPEC validations of canonical CPEC properties and functions Like mouse dCPECs 14 , human dCPEC islands formed three dimensional (3D) folds 18 and ridges over time and expressed established markers of several CPEC compartments by ICC (secretory apparatus/TTR 19 , apical membrane/AQP1 20 , basolateral membrane/AE2 21 , cilia/ARL13B 22 , nucleus/OTX2 23 , tight junctions/CLDN1 and CLDN5 24 ) in a stereotypical order (Figs. 1F; S1G).…”

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review

“…Since choroid plexus papilloma is regarded as a fully differentiated benign papillary neoplasm closely resembling non-neoplastic choroid plexus tissue, most studies on CSCs of choroid plexus tumours have focused on choroid plexus carcinoma [ 38 ]. The markers for CSCs in choroid plexus carcinoma are MYC, Nestin, ATOH1, BLBP, GFAP, Geminin, GDF7, and differentiation markers are mainly for choroid plexus epithelial cells, such as TTR, AQP1, OTX2, GMNC, MCIDAS, FOXJ1, CCNO, TAp73, and MYB [ 37 , 38 , 39 ].…”