Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development
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Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development. / Li, Qun; Han, Zhiyuan; Singh, Navleen; Terré, Berta; Fame, Ryann M; Arif, Uzayr; Page, Thomas D; Zahran, Tasneem; Abdeltawab, Ahmed; Huang, Yuan; Cao, Ping; Wang, Jun; Lu, Hao; Lidov, Hart G W; Surendran, Kameswaran; Wu, Lizhao; Virga, James Q; Zhao, Ying-Tao; Ulrich, Schüller; Wechsler-Reya, Robert J; Lehtinen, Maria K; Roy, Sudipto; Liu, Zhongmin; Stracker, Travis H; Zhao, Haotian.
in: CELL DEATH DIFFER, Jahrgang 29, Nr. 8, 08.2022, S. 1596-1610.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development
AU - Li, Qun
AU - Han, Zhiyuan
AU - Singh, Navleen
AU - Terré, Berta
AU - Fame, Ryann M
AU - Arif, Uzayr
AU - Page, Thomas D
AU - Zahran, Tasneem
AU - Abdeltawab, Ahmed
AU - Huang, Yuan
AU - Cao, Ping
AU - Wang, Jun
AU - Lu, Hao
AU - Lidov, Hart G W
AU - Surendran, Kameswaran
AU - Wu, Lizhao
AU - Virga, James Q
AU - Zhao, Ying-Tao
AU - Ulrich, Schüller
AU - Wechsler-Reya, Robert J
AU - Lehtinen, Maria K
AU - Roy, Sudipto
AU - Liu, Zhongmin
AU - Stracker, Travis H
AU - Zhao, Haotian
N1 - © 2022. The Author(s).
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Animals
KW - Carcinoma/genetics
KW - Cell Cycle Proteins/genetics
KW - Choroid Plexus Neoplasms/genetics
KW - Hedgehog Proteins/genetics
KW - Humans
KW - Mice
KW - Nuclear Proteins/genetics
U2 - 10.1038/s41418-022-00950-z
DO - 10.1038/s41418-022-00950-z
M3 - SCORING: Journal article
C2 - 35322202
VL - 29
SP - 1596
EP - 1610
JO - CELL DEATH DIFFER
JF - CELL DEATH DIFFER
SN - 1350-9047
IS - 8
ER -
