Sonic Hedgehog promotes proliferation of Notch-dependent monociliated choroid plexus tumour cells

Abstract Tumors of the choroid plexus (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 is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.

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Feasibility and value of preoperative embolization of a congenital choroid plexus tumour in the premature infant: An illustrative case report with technical details

Interventional Neuroradiology ◽

10.1177/1591019916665346 ◽

2016 ◽

Vol 22 (6) ◽

pp. 732-735 ◽

Cited By ~ 4

Author(s):

Tariq Aljared ◽

Jean-Pierre Farmer ◽

Donatella Tampieri

Keyword(s):

Choroid Plexus ◽

Choroid Plexus Papilloma ◽

Preoperative Embolization ◽

Haemodynamic Instability ◽

Illustrative Case ◽

Preterm Baby ◽

Vasogenic Oedema ◽

Estimated Blood Loss ◽

The Right ◽

Choroid Plexus Tumour

We present a case of a preterm boy (born at 35 weeks of pregnancy) who was delivered urgently by a caesarean section due to placental abruption. The baby was found to have a tense fontanelle leading to imaging that showed a 5.5 cm right intraventricular mass centred in the atrium, hydrocephalus and extensive surrounding vasogenic oedema. The mass was avidly enhancing with a few large associated vessels suggesting high vascularity. The condition of the baby was acutely deteriorating. He had multiple seizures followed by persistent low level of consciousness in the third day of life. His clinical decline prompted decision to proceed with surgical resection and preoperative embolization. A large single feeder (the right posterolateral choroidal artery) was embolized leading to near complete obliteration of the tumour blush. Embolization likely facilitated subsequent surgery the next day. This is based on an estimated blood loss of 250 ml in this 3 kg baby without haemodynamic instability. Gross total resection was achieved with a single surgery and the diagnosis was choroid plexus papilloma. Utilization of this combined approach in this preterm baby had led to survival in this potentially curable disease.

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Sonic hedgehog signaling regulates a novel epithelial progenitor domain of the hindbrain choroid plexus

Development ◽

10.1242/dev.033795 ◽

2009 ◽

Vol 136 (15) ◽

pp. 2535-2543 ◽

Cited By ~ 50

Author(s):

X. Huang ◽

T. Ketova ◽

J. T. Fleming ◽

H. Wang ◽

S. K. Dey ◽

...

Keyword(s):

Choroid Plexus ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Sonic Hedgehog Signaling ◽

Progenitor Domain

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Sonic hedgehog is required for vascular outgrowth in the hindbrain choroid plexus

Developmental Biology ◽

10.1016/j.ydbio.2010.01.032 ◽

2010 ◽

Vol 340 (2) ◽

pp. 430-437 ◽

Cited By ~ 42

Author(s):

Corinne M. Nielsen ◽

Susan M. Dymecki

Keyword(s):

Choroid Plexus ◽

Sonic Hedgehog

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RARE-14. DISRUPTION OF GEMC1-MCIDAS MULTICILIOGENESIS PROGRAM PROMOTES CHOROID PLEXUS CARCINOMA

Neuro-Oncology ◽

10.1093/neuonc/noab090.175 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i43-i43

Author(s):

Navleen Singh ◽

Tamanna Sarowar ◽

Tasneerm Zahran ◽

Haotian Zhao

Keyword(s):

Epithelial Cells ◽

Choroid Plexus ◽

Tumor Cells ◽

Sonic Hedgehog ◽

Hedgehog Signaling ◽

Coiled Coil ◽

Apical Surface ◽

Cell Cycle Protein ◽

Sonic Hedgehog Signaling ◽

Therapeutic Avenue

Abstract Tumors of the choroid plexus (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 is more benign, CPC is a highly lethal and little understood cancer with poor survival rate and a tendency for recurrence and metastasis. CP tumors are thought to arise from CP epithelial cells that secrets cerebral spinal fluid and generate multiple cilia on their apical surface. Here we show that aberrant NOTCH and Sonic Hedgehog signaling in mice drive tumors that resemble CPC in humans. In contrast to CP epithelial cells with clusters of multiple cilia, NOTCH-driven CP tumors were monociliated, and disruption of the NOTCH complex restored multiciliation and decreased tumor growth. NOTCH suppressed multiciliation in tumor cells by inhibiting the expression of Geminin Coiled-Coil Domain Containing 1 (GEMC1), and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS), early transcriptional regulators of multiciliated cell (MCC) differentiation. Consistently, Gemc1-Mcidas deficiency led to a lack of MCCs in the CP, and impaired the correction of the multiciliation defect in tumor cells by a NOTCH inhibitor. Disturbances to the GEMC1 program are commonly observed in human CPCs characterized by solitary cilia and frequent somatic TP53 mutations. Accordingly, CPC driven by deletion of tumor suppressors Trp53 and Rb1 in mice exhibits a cilia deficit consequent to loss of Gemc1-Mcidas expression. Taken together, these findings reveal that the GEMC1-MCIDAS multiciliogenesis program in the CP is critical for inhibiting tumorigenesis, whereas a defective multiciliation program promotes CPC and may represent a therapeutic avenue for this cancer.

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Von Hippel-Lindau disease associated with an invasive choroid plexus tumour presenting as a middle ear mass

The Journal of Laryngology & Otology ◽

10.1017/s0022215100119747 ◽

1992 ◽

Vol 106 (5) ◽

pp. 429-435 ◽

Cited By ~ 26

Author(s):

T. L. Blamires ◽

I. Friedmann ◽

D. A. Moffat

Keyword(s):

Choroid Plexus ◽

Middle Ear ◽

Von Hippel Lindau ◽

Von Hippel Lindau Disease ◽

Choroid Plexus Tumour

AbstractCerebellar haemangioblastomata and angiomata of the retina are the most common vascular tumours seen in von Hippel-Lindau disease. A definite association between this condition and choroid plexus tumour has not been described previously and its presentation as a middle ear mass is unique.

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