Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.
Journal
Cell death and differentiation
ISSN: 1476-5403
Titre abrégé: Cell Death Differ
Pays: England
ID NLM: 9437445
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
13
04
2021
accepted:
31
01
2022
revised:
17
01
2022
pubmed:
25
3
2022
medline:
5
8
2022
entrez:
24
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35322202
doi: 10.1038/s41418-022-00950-z
pii: 10.1038/s41418-022-00950-z
pmc: PMC9345885
doi:
Substances chimiques
Cell Cycle Proteins
0
Hedgehog Proteins
0
Mcidas protein, mouse
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1596-1610Subventions
Organisme : NIH HHS
ID : S10 OD016167
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103620
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL110852
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA220551
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS088566
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103548
Pays : United States
Informations de copyright
© 2022. The Author(s).
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