Nestin Mediates Hedgehog Pathway Tumorigenesis

Li, Peng; Lee, Eric H.; Du, Fang; Gordon, Renata E.; Yuelling, Larra W.; Liu, Yongqiang; Ng, Jessica M.Y.; Zhang, Hao; Wu, Jiangxue; Korshunov, Andrey; Pfister, Stefan M.; Curran, Tom; Yang, Zeng-jie

doi:10.1158/0008-5472.can-16-1547

Cited by 29 publications

(46 citation statements)

References 48 publications

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“…Recently we reported that Nestin expression level increase during tumor progression and that it plays a key role in enhancing hedgehog pathway activity and MB cell proliferation in vivo (22). Having observed that Shh can promote MB cell proliferation, we examined whether Shh affects Nestin expression in MB cells.…”

Section: Resultsmentioning

confidence: 99%

“…Ptch1 fl/fl mice, Nestin-CFP mice have been described previously (22). Math1-Cre Mice, Ptch1-lacZ mice, GFAP-GFP mice, GFAP-TK mice and Rosa26-SmoM2 mice were from Jackson Labs (Bar Harbor, ME).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported that expression of Nestin, a type VI intermediate filament protein, is required for Ptch1 -deficient GNPs to form MB. Nestin augmented hedgehog pathway activity by binding to Gli3, thereby abolishing its inhibitory function (22). These data reveal that Nestin expression is indispensable for MB tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

et al. 2017

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Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. While astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secreted the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drove expression of Nestin in MB cells through a Smoothened-dependent, Gli1-independent mechanism. Ablation of TAA dramatically suppressed Nestin expression and blocked tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

et al. 2017

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“…MELK interacts with EZH2 in Daoy and MB25550 CSCs, and the xenografts that develop from the two kinds of MBSCs are strongly attenuated by RNA knockdown or inhibitors. Initial findings have revealed Nestin-bound hedgehog pathway to promote the development of SHH-MB (45). The sample of SHH-MB in this research also displays the high expression of Nestin ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 50%

“…However, stem cell microenvironment has changed a great deal with the initiation and progression of neoplasms. Studies have suggested the vital role of tumor microenvironments that normally operate to regulate various types of protein stabilities during CSCs self-proliferation (45). CSCs are "clever" enough to modify the microenvironment by recruiting agents to make others, including vessels, astrocytes, fibroblasts, etc., serve themselves with the goal of maintaining self-renewal (46).…”

Section: Discussionmentioning

confidence: 99%

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Liu

Sun

et al. 2017

Molecular Cancer Research

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Medulloblastoma is the most common malignant brain tumor in children. Although accumulated research has suggested that cancer stem-like cells play a key role in medulloblastoma tumorigenesis, the specific molecular mechanism regarding proliferation remains elusive. Here, we reported more abundant expression of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) in medulloblastoma stemlike cells than in neural stem cells and the interaction between the two proteins could mediate the self-renewal of sonic hedgehog subtype medulloblastoma. In human medulloblastoma, extensive nodularity and large-cell/anaplastic subgroups differed according to the staining levels of MELK and EZH2 from the other two subgroups. The proportion of MELK-or EZH2-positive staining status could be considered as a potential indicator for survival. Mechanistically, MELK bound to and phosphorylated EZH2, and its methylation was induced by EZH2 in medulloblastoma, which could regulate the proliferation of cancer stemlike cells. In xenografts, loss of MELK or EZH2 attenuated medulloblastoma stem-like cell-derived tumor growth and promoted differentiation. These findings indicate that MELK-induced phosphorylation and EZH2-mediated methylation in MELK/EZH2 pathway are essential for medulloblastoma stem-like cell-derived tumor proliferation, thereby identifying a potential therapeutic strategy for these patients.Implications: This study demonstrates that the interaction occurring between MELK and EZH2 promotes self-proliferation and stemness, thus representing an attractive therapeutic target and potential candidate for diagnosis of medulloblastoma.Mol Cancer Res; 15(9); 1275-86. Ó2017 AACR.

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Principles of tumorigenesis and emerging molecular drivers of SHH‐activated medulloblastomas

Menyhárt

Győrffy

2019

Ann Clin Transl Neurol

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SHH ‐activated medulloblastomas ( SHH ‐ MB ) account for 25–30% of all medulloblastomas ( MB ) and occur with a bimodal age distribution, encompassing many infant and adult, but fewer childhood cases. Different age groups are characterized by distinct survival outcomes and age‐specific alterations of regulatory pathways. Here, we review SHH ‐specific genetic aberrations and signaling pathways. Over 95% of SHH ‐ MB s contain at least one driver event – the activating mutations frequently affect sonic hedgehog signaling ( PTCH 1, SMO , SUFU ), genome maintenance ( TP 53), and chromatin modulation ( KMT 2D, KMT 2C, HAT complexes), while genes responsible for transcriptional regulation ( MYCN ) are recurrently amplified. SHH ‐ MB s have the highest prevalence of damaging germline mutations among all MB s. TP 53‐mutant MB s are enriched among older children and have the worst prognosis among all SHH ‐ MB s. Numerous genetic aberrations, including mutations of TERT , DDX 3X, and the PI 3K/ AKT / mTOR pathway are almost exclusive to adult patients. We elaborate on the newest development within the evolution of molecular subclassification, and compare proposed risk categories across emerging classification systems. We discuss discoveries based on preclinical models and elaborate on the applicability of potential new therapies, including BET bromodomain inhibitors, statins, inhibitors of SMO , AURK , PLK , cMET , targeting stem‐like cells, and emerging immunotherapeutic strategies. An enormous amount of data on the genetic background of SHH ‐ MB have accumulated, nevertheless, subgroup affiliation does not provide reliable prediction about response to therapy. Emerging subtypes within SHH ‐ MB offer more layered risk stratifications. Rational clinical trial designs with the incorporation of available molecular knowledge are inevitable. Improved collaboration across the scientific community will be imperative for therapeutic breakthroughs.

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Nestin Mediates Hedgehog Pathway Tumorigenesis

Cited by 29 publications

References 48 publications

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

Astrocytes Promote Medulloblastoma Progression through Hedgehog Secretion

MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation

Principles of tumorigenesis and emerging molecular drivers of SHH‐activated medulloblastomas

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