The Experts below are selected from a list of 1338 Experts worldwide ranked by ideXlab platform

Haotian Zhao - One of the best experts on this subject based on the ideXlab platform.

  • pm 15notch and shh signaling pathways converge on the primary cilium to promote Choroid Plexus Tumor initiation from epithelial progenitors
    Neuro-oncology, 2015
    Co-Authors: Haotian Zhao, Katie Picotte, Jasmin Ohli, Jun Wang, Robert J Wechslerreya, Ulrich Schuller
    Abstract:

    Choroid Plexus (CP) Tumors are brain neoplasms arising from CP epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. While CP papilloma is benign, CP carcinoma is malignant and associated with poor prognosis. Previous studies have implicated Notch signaling in human CP Tumors. However, the cell of origin and mechanisms underlying Notch-induced CP Tumors remain unclear. We have developed novel mouse models of CP Tumor caused by sustained expression of Notch 1 that recapitulate properties of human CP Tumors with abnormal NOTCH signaling. While Tumor cells in our models expressed CP markers Lmx1a and Otx2, the expression of aquaporin 1 and transthyretin, markers for differentiated CP epithelium, was absent or significantly reduced. Gene expression profiling revealed that Tumor cell proliferation is accompanied by enhanced Sonic Hedgehog (Shh) signaling. Importantly, human CP Tumors with abnormal NOTCH pathway activities also exhibited increased SHH signaling. Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells, while inhibition of Shh signaling suppressed Tumor growth. Vertebrate Shh signaling is dependent on primary cilium. Unlike mature CP epithelial cells with clusters of primary cilia on cell surface, Notch-induced CP Tumor cells possess a solitary primary cilium. Further analysis showed reduced expression of genes involved in multiciliate differentiation in Tumor cells. Shh-driven signaling cascade in the primary cilium occured in Tumor cells but not in epithelial cells. Lineage studies showed that Notch-induced CP Tumor arose from mono-ciliated epithelial progenitors in roof plates characterized by elevated Notch signaling. Together, these results indicate that sustained activation of Notch signaling causes aberrant proliferation of epithelial progenitors, converting them into Tumor-initiating cells that retain the ability to transduce Shh signals in the local environment and allows for Shh-driven proliferation. Our studies demonstrate Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

  • pl 02notch mediated suppression of multiciliate differentiation promotes Choroid Plexus Tumor initiation from epithelial progenitor in response to shh signals
    Neuro-oncology, 2014
    Co-Authors: Katie Picotte, Jasmin Ohli, Ulrich Schuller, Haotian Zhao
    Abstract:

    Choroid Plexus (CP) Tumors are intraventricular papillary neoplasms mainly found in children. While CP papilloma is a benign Tumor, CP carcinoma is malignant and associated with poor prognosis. Though previous studies implicate Notch signaling in CP Tumorigenesis, the developmental origin and mechanisms of Notch-induced CP Tumors remain unclear. We used the Rosa26-NICD1 strain to express the intracellular domain of Notch 1 (NICD1) using Cre-loxP technologies. Hindbrain CP targeted for NICD1 expression developed abnormal growth consistent with CP papilloma. While Notch-induced CP Tumor cells expressed CP markers Lmx1a and Otx2, the expression of Aquaporin 1 (AQP1), marker for differentiated CP epithelium, was absent. Embryonic studies showed that CP Tumor arises during development and exhibit properties similar to those of CP epithelial progenitors. However, unlike progenitor cells, Tumor cells fail to exit the cell cycle and differentiate into mature CP epithelium. Gene expression studies revealed increased expression of Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in both Notch-induced CP Tumors and human CP Tumors, suggesting the role of Shh signaling in CP Tumors. Conversely, Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells. Vertebrate Shh signaling is uniquely dependent on primary cilium. Unlike differentiated CP epithelial cells with small tufts of primary cilia on their apical surface, Notch-induced CP Tumor cells only possess solitary primary cilium. Further analysis revealed reduced expression of Foxj1 and Mcidas, crucial regulators of multiciliate differentiation, in Tumor cells. Together, these results indicate that Notch-induced CP Tumor arises from CP epithelial progenitors during development but lack terminal differentiation; and Notch pathway activation in Tumor cells suppresses multiciliate differentiation, thereby allowing Shh-driven proliferation. Our studies demonstrate that Notch and Shh pathways converge on primary cilium to drive CP Tumor formation, Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

  • abstract b3 notch 1 signaling induced Choroid Plexus Tumor arises from epithelial progenitor via sonic hedgehog pathway
    Cancer Research, 2014
    Co-Authors: Katie Picotte, Brian Westerhuis, Haotian Zhao
    Abstract:

    Introduction: Choroid Plexus Tumors are rare intraventricular papillary neoplasms of the Choroid Plexus (CP) epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. Choroid Plexus papilloma is a benign Tumor, whereas Choroid Plexus carcinoma is malignant and most commonly found in pediatric population. Despite good prognosis for Choroid Plexus papilloma after complete surgical removal, partially resected or inaccessible Tumors, and Choroid Plexus carcinomas are often associated with poor outcomes. Multiple factors including Notch signaling have been implicated in CP Tumor development, however, the cell of origin and mechanisms of CP Tumor formation remain unclear. In this study, we developed a genetic model of CP Tumor induced by Notch pathway activation. Our studies indicate Notch-induced CP Tumor is closely related to CP development and is driven by Sonic Hedgehog (Shh) signaling pathway. Methods: Math1-Cre transgenic strain was bred with Rosa26-NICD1 strain that express Notch 1 intracellular domain (NICD1) in a Cre-dependent manner. Math1-Cre/Rosa26-NICD1 animals were further crossed to green fluorescent protein (GFP) Cre reporter (Rosa26-GFP) strain to label Math1-positive lineage from rhombic lip. Transgene expression was analyzed by immunostaining for GFP co-expressed with NICD1 from the Rosa26 locus. Tumor cell proliferation was measured by immunostaining for Ki67 and EdU incorporation assay. Cell differentiation and survival were determined by immunohistochemistry analysis of lineage markers expression and cleaved caspase 3 staining respectively. Gene expression was examined by quantitative RT-PCR analysis and immunostaining. Results: Math1-postive rhombic lip lineage was detected in a small fraction of Choroid Plexus epithelium of 4th ventricle. The Choroid Plexus cells derived from Math1+ neural progenitors expressed Lmx1a, Otx2, early markers for CP epithelial lineage, and Aquaporin 1 (AQP1), marker for differentiated CP epithelial cells. In Math1-Cre/Rosa26-NICD1 animals, an abnormal growth was observed in hindbrain CP derived from Math1-positive rhombic lip neural progenitors. EdU incorporation assay and Ki67 staining revealed papillary and intraventricular growth of epithelial cells that exhibited enhanced proliferation compared to control animals in early postnatal period. Though Tumor cells expressed Lmx1a, Otx2, they didn9t express AQP1 and MafB, marker for CP mesenchyme. Quantitative RT-PCR analysis revealed that the expression of transthyretin (Ttr), a CP epithelial marker, was reduced in CP Tumor cells, while the expression levels of Notch pathway target genes, Hes1 and Hes5, were increased in Tumor cells. Proliferating CP Tumor cells exhibited higher levels of expression for Gli1, MycN, effectors of the Shh signaling, indicating aberrant activation of Shh pathway. Conclusions: Math1-positive rhombic lip lineage contributes to CP epithelium and is sensitive to Notch 1-induced Tumor formation. We have developed a genetic model of CP Tumor that exhibits characteristics of pediatric CP Tumors. Notch 1-induced CP Tumor cells have properties of CP progenitors and lack terminal differentiation. These CP Tumors exhibit a transient enhanced proliferation synchronous with enhanced activity of the Shh pathway. Animal models of CP Tumors have great potential to facilitate the discovery and development molecular diagnostics and targeted therapies for these rare pediatric malignancies. Citation Format: Li Li, Katie Picotte, Brian Westerhuis, Haotian Zhao. Notch 1 signaling-induced Choroid Plexus Tumor arises from epithelial progenitor via Sonic Hedgehog pathway. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B3.

  • abstract 3095 notch induced Choroid Plexus Tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth
    Cancer Research, 2014
    Co-Authors: Haotian Zhao, Katie Picotte
    Abstract:

    Introduction: Choroid Plexus Tumors are rare intraventricular papillary neoplasms arising from Choroid Plexus (CP) epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. Choroid Plexus papilloma is a benign Tumor, whereas Choroid Plexus carcinoma is malignant and most commonly found in pediatric population. Knowledge of the oncogenic processes in CP Tumor formation will profoundly impact the development of new and molecular targeted therapies. Previous studies implicate Notch signaling in CP Tumorigenesis. However, mechanisms underlying Notch-driven CP Tumor formation remain unclear. Animal models of CP Tumors have great potential to facilitate the discovery and development of molecular diagnostics and targeted therapies for these rare diseases. Methods and Results: We used the Rosa26-NICD1 strain which will constitutively express the intracellular domain of Notch 1 (NICD1) from the Rosa26 locus after Cre-mediated DNA recombination. The hindbrain CP targeted for NICD1 expression was significantly enlarged with well circumscribed, globular, cauliflower like masses. Histological analysis revealed that CP from NICD1-expressing mutant mice contained an abnormal growth in the 4th ventricle consistent with properties of Choroid Plexus Tumor. Tumor cells exhibit enhanced proliferation transiently after birth: Tumor cell proliferation was highest at birth, then gradually decreased and completely stopped at 2 weeks after birth. While CP Tumor cells expressed early CP lineage markers such as Lmx1a and Otx2, they didn’t express Aquaporin 1 (AQP1), marker for differentiated CP epithelial cells, suggesting lack of terminal differentiation. We further showed that CP Tumor arises during development as ectopic Lmx1a+ cells in CP and exhibit properties similar to those of CP epithelium progenitors. However, unlike progenitor cells, Tumor cells fail to exit the cell cycle and differentiate into mature epithelial cells. We characterized changes in gene expression in Tumor cells by quantitative RT-PCR. Surprisingly, we detected increased levels of Shh, Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in proliferating Tumor cells. CP Tumor cells cultured in serum-free conditions underwent rapid proliferation in the presence of Shh. Ultra-structural studies revealed lack of multi-ciliation differentiation in Tumors cells, whereas the expression of Foxj1 and Midas, crucial regulators of cilia differentiation, was significantly downregulated. Conclusions: We developed a genetic model of CP Tumor driven by Notch signaling activation. Notch 1-induced CP Tumor arises during development from CP epithelial progenitors but lack terminal differentiation and multi-ciliation of mature CP epithelial cells. The proliferation of Notch 1-induced Tumors is supported by Shh pathway, indicating Shh pathway as a therapeutic target for Notch-driven CP Tumors. Citation Format: Haotian Zhao, Li Li, Katie Picotte. Notch-induced Choroid Plexus Tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3095. doi:10.1158/1538-7445.AM2014-3095

Katie Picotte - One of the best experts on this subject based on the ideXlab platform.

  • pm 15notch and shh signaling pathways converge on the primary cilium to promote Choroid Plexus Tumor initiation from epithelial progenitors
    Neuro-oncology, 2015
    Co-Authors: Haotian Zhao, Katie Picotte, Jasmin Ohli, Jun Wang, Robert J Wechslerreya, Ulrich Schuller
    Abstract:

    Choroid Plexus (CP) Tumors are brain neoplasms arising from CP epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. While CP papilloma is benign, CP carcinoma is malignant and associated with poor prognosis. Previous studies have implicated Notch signaling in human CP Tumors. However, the cell of origin and mechanisms underlying Notch-induced CP Tumors remain unclear. We have developed novel mouse models of CP Tumor caused by sustained expression of Notch 1 that recapitulate properties of human CP Tumors with abnormal NOTCH signaling. While Tumor cells in our models expressed CP markers Lmx1a and Otx2, the expression of aquaporin 1 and transthyretin, markers for differentiated CP epithelium, was absent or significantly reduced. Gene expression profiling revealed that Tumor cell proliferation is accompanied by enhanced Sonic Hedgehog (Shh) signaling. Importantly, human CP Tumors with abnormal NOTCH pathway activities also exhibited increased SHH signaling. Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells, while inhibition of Shh signaling suppressed Tumor growth. Vertebrate Shh signaling is dependent on primary cilium. Unlike mature CP epithelial cells with clusters of primary cilia on cell surface, Notch-induced CP Tumor cells possess a solitary primary cilium. Further analysis showed reduced expression of genes involved in multiciliate differentiation in Tumor cells. Shh-driven signaling cascade in the primary cilium occured in Tumor cells but not in epithelial cells. Lineage studies showed that Notch-induced CP Tumor arose from mono-ciliated epithelial progenitors in roof plates characterized by elevated Notch signaling. Together, these results indicate that sustained activation of Notch signaling causes aberrant proliferation of epithelial progenitors, converting them into Tumor-initiating cells that retain the ability to transduce Shh signals in the local environment and allows for Shh-driven proliferation. Our studies demonstrate Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

  • pl 02notch mediated suppression of multiciliate differentiation promotes Choroid Plexus Tumor initiation from epithelial progenitor in response to shh signals
    Neuro-oncology, 2014
    Co-Authors: Katie Picotte, Jasmin Ohli, Ulrich Schuller, Haotian Zhao
    Abstract:

    Choroid Plexus (CP) Tumors are intraventricular papillary neoplasms mainly found in children. While CP papilloma is a benign Tumor, CP carcinoma is malignant and associated with poor prognosis. Though previous studies implicate Notch signaling in CP Tumorigenesis, the developmental origin and mechanisms of Notch-induced CP Tumors remain unclear. We used the Rosa26-NICD1 strain to express the intracellular domain of Notch 1 (NICD1) using Cre-loxP technologies. Hindbrain CP targeted for NICD1 expression developed abnormal growth consistent with CP papilloma. While Notch-induced CP Tumor cells expressed CP markers Lmx1a and Otx2, the expression of Aquaporin 1 (AQP1), marker for differentiated CP epithelium, was absent. Embryonic studies showed that CP Tumor arises during development and exhibit properties similar to those of CP epithelial progenitors. However, unlike progenitor cells, Tumor cells fail to exit the cell cycle and differentiate into mature CP epithelium. Gene expression studies revealed increased expression of Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in both Notch-induced CP Tumors and human CP Tumors, suggesting the role of Shh signaling in CP Tumors. Conversely, Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells. Vertebrate Shh signaling is uniquely dependent on primary cilium. Unlike differentiated CP epithelial cells with small tufts of primary cilia on their apical surface, Notch-induced CP Tumor cells only possess solitary primary cilium. Further analysis revealed reduced expression of Foxj1 and Mcidas, crucial regulators of multiciliate differentiation, in Tumor cells. Together, these results indicate that Notch-induced CP Tumor arises from CP epithelial progenitors during development but lack terminal differentiation; and Notch pathway activation in Tumor cells suppresses multiciliate differentiation, thereby allowing Shh-driven proliferation. Our studies demonstrate that Notch and Shh pathways converge on primary cilium to drive CP Tumor formation, Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

  • abstract b3 notch 1 signaling induced Choroid Plexus Tumor arises from epithelial progenitor via sonic hedgehog pathway
    Cancer Research, 2014
    Co-Authors: Katie Picotte, Brian Westerhuis, Haotian Zhao
    Abstract:

    Introduction: Choroid Plexus Tumors are rare intraventricular papillary neoplasms of the Choroid Plexus (CP) epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. Choroid Plexus papilloma is a benign Tumor, whereas Choroid Plexus carcinoma is malignant and most commonly found in pediatric population. Despite good prognosis for Choroid Plexus papilloma after complete surgical removal, partially resected or inaccessible Tumors, and Choroid Plexus carcinomas are often associated with poor outcomes. Multiple factors including Notch signaling have been implicated in CP Tumor development, however, the cell of origin and mechanisms of CP Tumor formation remain unclear. In this study, we developed a genetic model of CP Tumor induced by Notch pathway activation. Our studies indicate Notch-induced CP Tumor is closely related to CP development and is driven by Sonic Hedgehog (Shh) signaling pathway. Methods: Math1-Cre transgenic strain was bred with Rosa26-NICD1 strain that express Notch 1 intracellular domain (NICD1) in a Cre-dependent manner. Math1-Cre/Rosa26-NICD1 animals were further crossed to green fluorescent protein (GFP) Cre reporter (Rosa26-GFP) strain to label Math1-positive lineage from rhombic lip. Transgene expression was analyzed by immunostaining for GFP co-expressed with NICD1 from the Rosa26 locus. Tumor cell proliferation was measured by immunostaining for Ki67 and EdU incorporation assay. Cell differentiation and survival were determined by immunohistochemistry analysis of lineage markers expression and cleaved caspase 3 staining respectively. Gene expression was examined by quantitative RT-PCR analysis and immunostaining. Results: Math1-postive rhombic lip lineage was detected in a small fraction of Choroid Plexus epithelium of 4th ventricle. The Choroid Plexus cells derived from Math1+ neural progenitors expressed Lmx1a, Otx2, early markers for CP epithelial lineage, and Aquaporin 1 (AQP1), marker for differentiated CP epithelial cells. In Math1-Cre/Rosa26-NICD1 animals, an abnormal growth was observed in hindbrain CP derived from Math1-positive rhombic lip neural progenitors. EdU incorporation assay and Ki67 staining revealed papillary and intraventricular growth of epithelial cells that exhibited enhanced proliferation compared to control animals in early postnatal period. Though Tumor cells expressed Lmx1a, Otx2, they didn9t express AQP1 and MafB, marker for CP mesenchyme. Quantitative RT-PCR analysis revealed that the expression of transthyretin (Ttr), a CP epithelial marker, was reduced in CP Tumor cells, while the expression levels of Notch pathway target genes, Hes1 and Hes5, were increased in Tumor cells. Proliferating CP Tumor cells exhibited higher levels of expression for Gli1, MycN, effectors of the Shh signaling, indicating aberrant activation of Shh pathway. Conclusions: Math1-positive rhombic lip lineage contributes to CP epithelium and is sensitive to Notch 1-induced Tumor formation. We have developed a genetic model of CP Tumor that exhibits characteristics of pediatric CP Tumors. Notch 1-induced CP Tumor cells have properties of CP progenitors and lack terminal differentiation. These CP Tumors exhibit a transient enhanced proliferation synchronous with enhanced activity of the Shh pathway. Animal models of CP Tumors have great potential to facilitate the discovery and development molecular diagnostics and targeted therapies for these rare pediatric malignancies. Citation Format: Li Li, Katie Picotte, Brian Westerhuis, Haotian Zhao. Notch 1 signaling-induced Choroid Plexus Tumor arises from epithelial progenitor via Sonic Hedgehog pathway. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B3.

  • abstract 3095 notch induced Choroid Plexus Tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth
    Cancer Research, 2014
    Co-Authors: Haotian Zhao, Katie Picotte
    Abstract:

    Introduction: Choroid Plexus Tumors are rare intraventricular papillary neoplasms arising from Choroid Plexus (CP) epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. Choroid Plexus papilloma is a benign Tumor, whereas Choroid Plexus carcinoma is malignant and most commonly found in pediatric population. Knowledge of the oncogenic processes in CP Tumor formation will profoundly impact the development of new and molecular targeted therapies. Previous studies implicate Notch signaling in CP Tumorigenesis. However, mechanisms underlying Notch-driven CP Tumor formation remain unclear. Animal models of CP Tumors have great potential to facilitate the discovery and development of molecular diagnostics and targeted therapies for these rare diseases. Methods and Results: We used the Rosa26-NICD1 strain which will constitutively express the intracellular domain of Notch 1 (NICD1) from the Rosa26 locus after Cre-mediated DNA recombination. The hindbrain CP targeted for NICD1 expression was significantly enlarged with well circumscribed, globular, cauliflower like masses. Histological analysis revealed that CP from NICD1-expressing mutant mice contained an abnormal growth in the 4th ventricle consistent with properties of Choroid Plexus Tumor. Tumor cells exhibit enhanced proliferation transiently after birth: Tumor cell proliferation was highest at birth, then gradually decreased and completely stopped at 2 weeks after birth. While CP Tumor cells expressed early CP lineage markers such as Lmx1a and Otx2, they didn’t express Aquaporin 1 (AQP1), marker for differentiated CP epithelial cells, suggesting lack of terminal differentiation. We further showed that CP Tumor arises during development as ectopic Lmx1a+ cells in CP and exhibit properties similar to those of CP epithelium progenitors. However, unlike progenitor cells, Tumor cells fail to exit the cell cycle and differentiate into mature epithelial cells. We characterized changes in gene expression in Tumor cells by quantitative RT-PCR. Surprisingly, we detected increased levels of Shh, Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in proliferating Tumor cells. CP Tumor cells cultured in serum-free conditions underwent rapid proliferation in the presence of Shh. Ultra-structural studies revealed lack of multi-ciliation differentiation in Tumors cells, whereas the expression of Foxj1 and Midas, crucial regulators of cilia differentiation, was significantly downregulated. Conclusions: We developed a genetic model of CP Tumor driven by Notch signaling activation. Notch 1-induced CP Tumor arises during development from CP epithelial progenitors but lack terminal differentiation and multi-ciliation of mature CP epithelial cells. The proliferation of Notch 1-induced Tumors is supported by Shh pathway, indicating Shh pathway as a therapeutic target for Notch-driven CP Tumors. Citation Format: Haotian Zhao, Li Li, Katie Picotte. Notch-induced Choroid Plexus Tumor arises from epithelial progenitor and depends on sonic hedgehog signaling for growth. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3095. doi:10.1158/1538-7445.AM2014-3095

Ulrich Schuller - One of the best experts on this subject based on the ideXlab platform.

  • pm 15notch and shh signaling pathways converge on the primary cilium to promote Choroid Plexus Tumor initiation from epithelial progenitors
    Neuro-oncology, 2015
    Co-Authors: Haotian Zhao, Katie Picotte, Jasmin Ohli, Jun Wang, Robert J Wechslerreya, Ulrich Schuller
    Abstract:

    Choroid Plexus (CP) Tumors are brain neoplasms arising from CP epithelium. They occur most often in childhood and comprise 10-20% of all brain Tumors in infants. While CP papilloma is benign, CP carcinoma is malignant and associated with poor prognosis. Previous studies have implicated Notch signaling in human CP Tumors. However, the cell of origin and mechanisms underlying Notch-induced CP Tumors remain unclear. We have developed novel mouse models of CP Tumor caused by sustained expression of Notch 1 that recapitulate properties of human CP Tumors with abnormal NOTCH signaling. While Tumor cells in our models expressed CP markers Lmx1a and Otx2, the expression of aquaporin 1 and transthyretin, markers for differentiated CP epithelium, was absent or significantly reduced. Gene expression profiling revealed that Tumor cell proliferation is accompanied by enhanced Sonic Hedgehog (Shh) signaling. Importantly, human CP Tumors with abnormal NOTCH pathway activities also exhibited increased SHH signaling. Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells, while inhibition of Shh signaling suppressed Tumor growth. Vertebrate Shh signaling is dependent on primary cilium. Unlike mature CP epithelial cells with clusters of primary cilia on cell surface, Notch-induced CP Tumor cells possess a solitary primary cilium. Further analysis showed reduced expression of genes involved in multiciliate differentiation in Tumor cells. Shh-driven signaling cascade in the primary cilium occured in Tumor cells but not in epithelial cells. Lineage studies showed that Notch-induced CP Tumor arose from mono-ciliated epithelial progenitors in roof plates characterized by elevated Notch signaling. Together, these results indicate that sustained activation of Notch signaling causes aberrant proliferation of epithelial progenitors, converting them into Tumor-initiating cells that retain the ability to transduce Shh signals in the local environment and allows for Shh-driven proliferation. Our studies demonstrate Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

  • pl 02notch mediated suppression of multiciliate differentiation promotes Choroid Plexus Tumor initiation from epithelial progenitor in response to shh signals
    Neuro-oncology, 2014
    Co-Authors: Katie Picotte, Jasmin Ohli, Ulrich Schuller, Haotian Zhao
    Abstract:

    Choroid Plexus (CP) Tumors are intraventricular papillary neoplasms mainly found in children. While CP papilloma is a benign Tumor, CP carcinoma is malignant and associated with poor prognosis. Though previous studies implicate Notch signaling in CP Tumorigenesis, the developmental origin and mechanisms of Notch-induced CP Tumors remain unclear. We used the Rosa26-NICD1 strain to express the intracellular domain of Notch 1 (NICD1) using Cre-loxP technologies. Hindbrain CP targeted for NICD1 expression developed abnormal growth consistent with CP papilloma. While Notch-induced CP Tumor cells expressed CP markers Lmx1a and Otx2, the expression of Aquaporin 1 (AQP1), marker for differentiated CP epithelium, was absent. Embryonic studies showed that CP Tumor arises during development and exhibit properties similar to those of CP epithelial progenitors. However, unlike progenitor cells, Tumor cells fail to exit the cell cycle and differentiate into mature CP epithelium. Gene expression studies revealed increased expression of Gli1 and N-Myc, effectors of the Sonic Hedgehog (Shh) pathway, in both Notch-induced CP Tumors and human CP Tumors, suggesting the role of Shh signaling in CP Tumors. Conversely, Shh treatment stimulated the proliferation of Notch-induced CP Tumor cells. Vertebrate Shh signaling is uniquely dependent on primary cilium. Unlike differentiated CP epithelial cells with small tufts of primary cilia on their apical surface, Notch-induced CP Tumor cells only possess solitary primary cilium. Further analysis revealed reduced expression of Foxj1 and Mcidas, crucial regulators of multiciliate differentiation, in Tumor cells. Together, these results indicate that Notch-induced CP Tumor arises from CP epithelial progenitors during development but lack terminal differentiation; and Notch pathway activation in Tumor cells suppresses multiciliate differentiation, thereby allowing Shh-driven proliferation. Our studies demonstrate that Notch and Shh pathways converge on primary cilium to drive CP Tumor formation, Shh pathway is a potential therapeutic target for Notch-induced CP Tumors.

Cynthia Hawkins - One of the best experts on this subject based on the ideXlab platform.

  • correction to dna methylation signature is prognostic of Choroid Plexus Tumor aggressiveness
    Clinical Epigenetics, 2019
    Co-Authors: Malgorzata Pienkowska, Sanaa Choufani, Andrei L Turinsky, Tanya Guha, Diana M Merino, Ana Novokmet, Michael Brudno, Rosanna Weksberg, Adam Shlien, Cynthia Hawkins
    Abstract:

    After publication of the original article [1], authors have requested to add a ‘J’ as middle name for Richard Gilbertson. Hence, full name should be Richard J Gilbertson.

  • dna methylation signature is prognostic of Choroid Plexus Tumor aggressiveness
    Clinical Epigenetics, 2019
    Co-Authors: Malgorzata Pienkowska, Sanaa Choufani, Andrei L Turinsky, Tanya Guha, Diana M Merino, Ana Novokmet, Michael Brudno, Rosanna Weksberg, Adam Shlien, Cynthia Hawkins
    Abstract:

    Histological grading of Choroid Plexus Tumors (CPTs) remains the best prognostic tool to distinguish between aggressive Choroid Plexus carcinoma (CPC) and the more benign Choroid Plexus papilloma (CPP) or atypical Choroid Plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child’s brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs. We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT Tumors obtained from Neuropathology, University Hospital Munster, Germany. Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment. We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive Tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.

Roosmarijn E Vandenbroucke - One of the best experts on this subject based on the ideXlab platform.

  • Choroid Plexus Tumor necrosis factor receptor 1 a new neuroinflammatory piece of the complex alzheimer s disease puzzle
    Neural Regeneration Research, 2019
    Co-Authors: Sophie Steeland, Roosmarijn E Vandenbroucke
    Abstract:

    Due to the aging of the population and despite the enormous scientific effort, Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease. Tumor necrosis factor is a master inflammatory cytokine that signals via Tumor necrosis factor receptor 1 and Tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the Tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results, partially because not only the pro-inflammatory Tumor necrosis factor/Tumor necrosis factor receptor 1, but also the beneficial Tumor necrosis factor/Tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that Tumor necrosis factor is the main upregulated cytokine in the Choroid Plexus of Alzheimer's disease patients, signaling via Tumor necrosis factor receptor 1. In agreement with this, Choroidal Tumor necrosis factor/Tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of Tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation, Choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by Tumor necrosis factor/Tumor necrosis factor receptor 1 signaling in (early) Alzheimer's disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.

  • Choroid Plexus Tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer’s disease puzzle
    Medknow Publications, 2019
    Co-Authors: Sophie Steeland, Roosmarijn E Vandenbroucke
    Abstract:

    Due to the aging of the population and despite the enormous scientific effort, Alzheimer’s disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer’s disease. Tumor necrosis factor is a master inflammatory cytokine that signals via Tumor necrosis factor receptor 1 and Tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the Tumor necrosis factor pathway in Alzheimer’s disease led to inconclusive results, partially because not only the pro-inflammatory Tumor necrosis factor/Tumor necrosis factor receptor 1, but also the beneficial Tumor necrosis factor/Tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that Tumor necrosis factor is the main upregulated cytokine in the Choroid Plexus of Alzheimer’s disease patients, signaling via Tumor necrosis factor receptor 1. In agreement with this, Choroidal Tumor necrosis factor/Tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer’s disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of Tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer’s disease-associated inflammation, Choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by Tumor necrosis factor/Tumor necrosis factor receptor 1 signaling in (early) Alzheimer’s disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer’s disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer’s disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer’s disease and prevent the irreversible neurodegeneration and resulting memory decline