Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.
Disruption of GMNC-MCIDAS multiciliogenesis program is critical in choroid plexus carcinoma development.
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DOI：
10.1038/s41418-022-00950-z
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发表时间：
2022-08
影响因子：
12.4
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Li Q;Han Z;Singh N;Terré B;Fame RM;Arif U;Page TD;Zahran T;Abdeltawab A;Huang Y;Cao P;Wang J;Lu H;Lidov HGW;Surendran K;Wu L;Virga JQ;Zhao YT;Schüller U;Wechsler-Reya RJ;Lehtinen MK;Roy S;Liu Z;Stracker TH;Zhao H
大脑中的多纤毛细胞（MCCs）位于室管膜和脉络丛（CP）上皮中。CP分泌脑脊液，在室管膜纤毛运动的驱动下在脑室系统内循环。CP肿瘤是一种罕见的原发性脑肿瘤，主要见于儿童。CP肿瘤有三种形式：CP乳头状瘤（CPP）、非典型CPP和CP癌（CPC）。虽然CPP和非典型CPP通常是良性的，可以通过手术解决，但CPC是一种特别具有侵袭性且很少了解的癌症，生存率低，有复发和转移的趋势。与CP上皮中的MCC相反，人类中的CPC的特征在于孤立纤毛、频繁的TP 53突变以及对由GMNC-MCIDAS转录网络指导的多纤毛发生程序的干扰。GMNC和MCIDAS是不同组织中MCC命运分化的早期转录调节因子。一致的是，GMNC-MCIDAS转录程序的组件在CP发育过程中表达，并且是CP中多细胞化所需的，而在小鼠中由Trp 53和Rb 1缺失驱动的CPC表现出多细胞化缺陷，这是由于GMNC-MCIDAS程序中的缺陷。先前的研究表明，NOTCH通路的异常激活导致CPP。在这里，我们表明，小鼠中NOTCH和Sonic Hedgehog信号传导的组合缺陷产生了与人类CPC相似的肿瘤。NOTCH驱动的CP肿瘤是单纤毛的，并且NOTCH复合体的破坏恢复多纤毛并降低肿瘤生长。NOTCH通过抑制GMNC和MCIDAS的表达来抑制肿瘤细胞中的多细胞形成，而Gmnc-Mcidas过表达挽救多细胞形成缺陷并抑制肿瘤细胞增殖。总之，这些发现表明，GMNC-MCIDAS多纤毛发生程序的重新激活对于抑制CP中的肿瘤发生至关重要，并且它可能对CPC的治疗具有治疗意义。
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.
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影响因子：
3.9
作者：
Amer N;Taha H;Hesham D;Al-Shehaby N;Mosaab A;Soudy M;Osama A;Mahmoud N;Elayadi M;Youssef A;Elbeltagy M;Zaghloul MS;Magdeldin S;Sayed AA;El-Naggar S
通讯作者：
El-Naggar S
影响因子：
3.2
作者：
Gozali, Alexa E.;Britt, Barbara;Finlay, Jonathan L.
通讯作者：
Finlay, Jonathan L.
影响因子：
4.6
作者：
Chizhikov, Victor V.;Lindgren, Anne G.;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
DOI：
10.1080/23262133.2016.1172747
发表时间：
2016-01-01
期刊：
Neurogenesis (Austin, Tex.)
影响因子：
--
作者：
Kyrousi, Christina;Lalioti, Maria-Eleni;Taraviras, Stavros
通讯作者：
Taraviras, Stavros
影响因子：
6.2
作者：
Lalioti, Maria-Eleni;Kaplani, Konstantina;Taraviras, Stavros
通讯作者：
Taraviras, Stavros