A Drosophila Model for EGFR-Ras and PI3K-Dependent Human Glioma

Read, Renee D.; Cavenee, Webster K.; Furnari, Frank B.; Thomas, John B.

doi:10.1371/journal.pgen.1000374

Title: A Drosophila Model for EGFR-Ras and PI3K-Dependent Human Glioma

Journal Article · 12 February 2009 · PLoS Genetics

DOI: https://doi.org/10.1371/journal.pgen.1000374 · OSTI ID:1627273

Read, Renee D. ^[1]; Cavenee, Webster K. ^[2]; Furnari, Frank B. ^[3]; Thomas, John B. ^[4]

Salk Institute for Biological Studies, La Jolla, CA (United States). Molecular Neurobiology Lab.; DOE/OSTI
Univ. of California, San Diego, La Jolla, CA (United States). Ludwig Inst. for Cancer Research; Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Medicine; Univ. of California, San Diego, La Jolla, CA (United States). Cancer Center; Univ. of California, San Diego, La Jolla, CA (United States). Center for Molecular Genetics
Univ. of California, San Diego, La Jolla, CA (United States). Ludwig Inst. for Cancer Research; Univ. of California, San Diego, La Jolla, CA (United States). Dept. of Medicine; Univ. of California, San Diego, La Jolla, CA (United States). Cancer Center
Salk Institute for Biological Studies, La Jolla, CA (United States). Molecular Neurobiology Lab.

Gliomas, the most common malignant tumors of the nervous system, frequently harbor mutations that activate the epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling pathways. To investigate the genetic basis of this disease, we developed a glioma model in Drosophila. We found that constitutive coactivation of EGFRRas and PI3K pathways in Drosophila glia and glial precursors gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking human glioma. Our model represents a robust organotypic and cell-type specific Drosophila cancer model in which malignant cells are created by mutations in signature genes and pathways thought to be driving forces in a homologous human cancer. Genetic analyses demonstrated that EGFR and PI3K initiate malignant neoplastic transformation via a combinatorial genetic network composed primarily of other pathways commonly mutated or activated in human glioma, including the Tor, Myc, G1 Cyclins-Cdks, and Rb-E2F pathways. This network acts synergistically to coordinately stimulate cell cycle entry and progression, protein translation, and inappropriate cellular growth and migration. In particular, we found that the fly orthologs of CyclinE, Cdc25, and Myc are key rate-limiting genes required for glial neoplasia. Moreover, orthologs of Sin1, Rictor, and Cdk4 are genes required only for abnormal neoplastic glial proliferation but not for glial development. These and other genes within this network may represent important therapeutic targets in human glioma.

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Research Organization:: Salk Institute for Biological Studies, La Jolla, CA (United States); Univ. of California, San Diego, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

OSTI ID:: 1627273

Journal Information:: PLoS Genetics, Journal Name: PLoS Genetics Journal Issue: 2 Vol. 5; ISSN 1553-7404

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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An integrative approach to ortholog prediction for disease-focused and other functional studies Hu, Yanhui; Flockhart, Ian; Vinayagam, Arunachalam BMC Bioinformatics, Vol. 12, Issue 1 https://doi.org/10.1186/1471-2105-12-357	journal	January 2011
Evolutionary history of phosphatidylinositol- 3-kinases: ancestral origin in eukaryotes and complex duplication patterns Philippon, Héloïse; Brochier-Armanet, Céline; Perrière, Guy BMC Evolutionary Biology, Vol. 15, Issue 1 https://doi.org/10.1186/s12862-015-0498-7	journal	October 2015
Pvr receptor tyrosine kinase signaling promotes post-embryonic morphogenesis, and survival of glia and neural progenitor cells in Drosophila Read, Renee D. Development, Vol. 145, Issue 23 https://doi.org/10.1242/dev.164285	journal	October 2018
Experimental models and tools to tackle glioblastoma Robertson, Faye L.; Marqués-Torrejón, Maria-Angeles; Morrison, Gillian M. Disease Models & Mechanisms, Vol. 12, Issue 9 https://doi.org/10.1242/dmm.040386	journal	September 2019
Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration Portela, Marta; Venkataramani, Varun; Fahey-Lozano, Natasha PLOS Biology, Vol. 17, Issue 12 https://doi.org/10.1371/journal.pbio.3000545	journal	December 2019
A Kinome-Wide RNAi Screen in Drosophila Glia Reveals That the RIO Kinases Mediate Cell Proliferation and Survival through TORC2-Akt Signaling in Glioblastoma Read, Renee D.; Fenton, Tim R.; Gomez, German G. PLoS Genetics, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pgen.1003253	journal	February 2013
Ras/ERK-signalling promotes tRNA synthesis and growth via the RNA polymerase III repressor Maf1 in Drosophila Sriskanthadevan-Pirahas, Shrivani; Deshpande, Rujuta; Lee, Byoungchun PLOS Genetics, Vol. 14, Issue 2 https://doi.org/10.1371/journal.pgen.1007202	journal	February 2018
WNT vampirization by glioblastoma leads to tumor growth and neurodegeneration Portela-Esteban, Marta; Venkataramani, Varun; Fahey-Lozano, Natasha La Trobe https://doi.org/10.26181/6004ef260c4d4	text	January 2021
Glioblastoma cells vampirize WNT from neurons and trigger a JNK/MMP signaling loop that enhances glioblastoma progression and neurodegeneration Portela-Esteban, Marta; Venkataramani, V.; Fahey-Lozano, Natalia La Trobe https://doi.org/10.26181/600502017b652	text	January 2021
Modelling Cooperative Tumorigenesis in Drosophila Richardson, Helena; Portela-Esteban, Marta La Trobe https://doi.org/10.26181/60135e070f52d	text	January 2021
Metabolic Reprogramming in Glioma Strickland, Marie; Stoll, Elizabeth A. Frontiers in Cell and Developmental Biology, Vol. 5 https://doi.org/10.3389/fcell.2017.00043	journal	April 2017
Drosophila melanogaster: A Model Organism to Study Cancer Mirzoyan, Zhasmine; Sollazzo, Manuela; Allocca, Mariateresa Frontiers in Genetics, Vol. 10 https://doi.org/10.3389/fgene.2019.00051	journal	March 2019

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