Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

Furnari, Frank B.; Cloughesy, Timothy F.; Cavenee, Webster K.; Mischel, Paul S.

doi:10.1038/nrc3918

Cited by 325 publications

(315 citation statements)

References 89 publications

(128 reference statements)

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“…In our experiments, we set out to use patient-derived tumor cells with genetically defined malignancy drivers for siRNA targeting. Given that intratumoral heterogeneity is likely unavoidable (49,64,65), subpopulations of BTICs independent of TFs within the tumor would likely overtake the growth even if siRNA combination therapies are effective in suppressing the BTIC populations dependent on TFs (66,67). This likelihood leads to the prospect of further combined targeting of adaptive malignancy drivers in response to TF suppression as an additional strategy toward personalized precision medicine.…”

Section: Discussionmentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood-brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTICtargeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.siRNA | lipopolymeric nanoparticle | glioblastoma transcription factor | brain tumor-initiating cells | convection-enhanced delivery G lioblastoma (GBM) is one of the most challenging tumors to treat (1, 2). Despite decades of research and maximal clinical combination therapy encompassing surgical resection, chemotherapy, and radiation, the median life expectancy of patients has not been extended beyond 2 y after diagnosis (2). Increasing evidence suggests that the genetic, epigenetic, and signaling heterogeneity of GBM underlies the ineffectiveness of currently available therapeutics (1, 2). Additionally, therapeutic schemes devised to challenge brain tumor cells are frequently thwarted by insufficient delivery caused by pharmacokinetics, the blood-brain barrier (BBB), and an altered tumor microenvironment in which tumor-derived signaling recruits immunomodulatory cells and induces extracellular matrix remodeling to build safe harbors of tumorigenic niches (3-5). These obstacles call for tailored therapeutic strategies to counter tumor heterogeneity and overcome roadblocks in delivery. RNAi targeting drivers of tumorigenesis shows strong potential to supplement the development of traditional small-molecule pharmaceutics (6). However, delivery remains a key obstacle for efficient RNAi against tumor drivers (5,7,8). RNA-sequencing analysis of patient tissue combined with histology and in situ hybridization (Ivy Glioblastoma Atlas Pro...

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Section: Discussionmentioning

confidence: 99%

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Khan

Suvà

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

112

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“…RTK-activated pathways are hyperactive in GBM, including Epidermal Growth Factor (EGF) Receptor and c-Met signaling. [10][11][12] Hepatocyte Growth Factor (HGF) and its receptor c-Met are both overexpressed in GBM, contributing to tumor growth invasion, angiogenesis and conferring a stem-like phenotype and poor prognosis. 10,[13][14][15][16] Although activating mutations of b-catenin have not been identified in GBM 17 , overexpression of b-catenin and other Wnt pathway components (including Fz 18 ) together with epigenetic regulation of Wnt inhibitors results in Wnt/ b-catenin activation in GBM.…”

Section: Introductionmentioning

confidence: 99%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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“…28,29 In addition, overexpression of the EGFR gene occurs across a wide range of different cancers, including brain, colorectal, lung, esophageal, cervical cancers, and sarcoma. [30][31][32][33][34][35] CDH1 and VEGFA have been reported among the highly significant markers in colorectal, gastric, and liver cancers. [36][37][38][39][40][41] The 154-gene expression signature shows clear promise in identifying the tumor's origin, but it is not perfect.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer transcriptome analysis reveals a gene expression signature for the identification of tumor tissue origin

Xu¹,

Chen²,

et al. 2016

Modern Pathology

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Carcinoma of unknown primary, wherein metastatic disease is present without an identifiable primary site, accounts for~3-5% of all cancer diagnoses. Despite the development of multiple diagnostic workups, the success rate of primary site identification remains low. Determining the origin of tumor tissue is, thus, an important clinical application of molecular diagnostics. Previous studies have paved the way for gene expression-based tumor type classification. In this study, we have established a comprehensive database integrating microarray-and sequencing-based gene expression profiles of 16 674 tumor samples covering 22 common human tumor types. From this pan-cancer transcriptome database, we identified a 154-gene expression signature that discriminated the origin of tumor tissue with an overall leave-one-out cross-validation accuracy of 96.5%. The 154-gene expression signature was first validated on an independent test set consisting of 9626 primary tumors, of which 97.1% of cases were correctly classified. Furthermore, we tested the signature on a spectrum of diagnostically challenging tumors. An overall accuracy of 92% was achieved on the 1248 tumor specimens that were poorly differentiated, undifferentiated or from metastatic tumors. Thus, we have identified a 154-gene expression signature that can accurately classify a broad spectrum of tumor types. This gene panel may hold a promise to be a useful additional tool for the determination of the tumor origin.

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Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma

Cited by 325 publications

References 89 publications

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Pan-cancer transcriptome analysis reveals a gene expression signature for the identification of tumor tissue origin

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