Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

Cruickshanks, Nichola; Zhang, Ying; Yuan, Fang; Pahuski, Mary; Gibert, Myron; Abounader, Roger

doi:10.3390/cancers9070087

Cited by 63 publications

(48 citation statements)

References 90 publications

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“…We demonstrate that GBM cells exposed to the secretome of the endothelial networks proliferated more than tumor cells exposed to control media, as well as exhibited decreased metabolic activity. Prior literature demonstrates that IGFBP2 and HGF support GBM proliferation, which supports the results obtained here [51,57]. In a previous study, we used RNA-seq to demonstrate that transcriptomic signatures are altered by interactions between GBM cells and endothelial networks cultured in the same hydrogel [31].…”

Section: Discussionsupporting

confidence: 88%

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

Ngo

Karvelis

Harley

2020

Preprint

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Glioblastoma is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche are largely unknown. Soluble angiocrine factors secreted by tumor-associated vasculature have been shown to support such behaviors in other cancer types. Here, we exploit macroscopic and microfluidic gelatin hydrogel platforms to profile angiocrine factors secreted by self-assembled endothelial networks and evaluate their relevance to glioblastoma biology.Aggregate angiocrine factors support U87-MG proliferation, migration, and therapeutic resistance to temozolomide. We also identify a novel role for TIMP1 in facilitating glioblastoma tumor cell migration. Overall, this work highlights the use of multidimensional hydrogel models to evaluate the role of angiocrine signals in glioblastoma progression. Glioblastoma progression is linked to interactions between tumor and vascular cells, which caninfluence invasion and therapeutic response. In co-culture studies to investigate tumor-vascular crosstalk, endothelial cells often are not presented in three-dimensional structures mimicking vasculature and the exact identity of secreted factors is not explored. Here, we use tissue engineering strategies to generate three-dimensional endothelial networks from which to collect soluble angiocrine signals and assess the impact of these signals on glioblastoma behavior. Furthermore, we use secretomic analysis to identify specific factors influencing glioblastoma

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Section: Discussionsupporting

confidence: 88%

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

Ngo

Karvelis

Harley

2020

Preprint

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“…New therapies targeting common aberrations in signal transduction pathways in GBM are currently being investigated (3). Dysregulation of receptor tyrosine kinases (RTK) have been found in approximately 90% of GBM (4,5). Consequently, tyrosine kinase inhibitors have been developed for anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…MET is commonly dysregulated in GBM via various mechanisms including somatic mutations, rearrangement, amplification and overexpression of MET and HGF that leads to autocrine loop formation (10)(11)(12). Furthermore, MET expression inversely correlates with patient survival (12,13) and is upregulated in GBM (5,14,15).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Cruickshanks

Zhang

Hine

et al. 2019

Clinical Cancer Research

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Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance. We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM. We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.

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“…c-Met and its only ligand, hepatocyte growth factor (HGF), have been proved to be connected with many physiological and pathological processes 27 . Alterations in HGF or c-Met are observed to be connected with more aggressive clinical behavior, contribute to cancer progression and influence patients’ prognosis in high grade glioma 9, 28 . Therefore, finding out the relationship of c-Met and high grade glioma will contribute to facilitating the discovery of more effective diagnostic method, therapeutics and predicting prognosis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

Zhong

et al. 2019

Preprint

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4Objectives: This study aims to assess the relationship between the expression of c-Met 5 and the prognosis of high grade glioma patients. 6 Method: The MET proto-oncogene encoded c-Met protein. The gene expression data 7 of 325 patients were downloaded from CGGA. The Oncomine database analysis and 8 the prognosis analysis were conducted. Besides, meta-analysis was also performed to 9 confirm the conclusion. 10 Result: Oncomine database was identified and analyzed and results showed that the 11 MET copy number was obviously higher in glioblastoma than normal tissue 12 consistently (p<0.001). The prognostic analysis of 325 high grade glioma samples 13 showed that high c-Met expression patients had poor overall survival (OS) and 14 progression free survival (PFS) than the low c-Met expression patients dramatically 15 (HR, 2.223; 95% CI: 1.662 to 2.974; P<0.0001 and HR, 2.089; 95% CI: 1.578 to 2.770; 16 P<0.0001). 6 studies involving 503 patients were included in the meta-analysis. The 17 pooled results indicated that the high expression of c-Met was not significantly 18 associated with OS (HR =1.01, 95% CI:0.93-1.09), but strongly connected with shorter 19 PFS (HR =1.92, 95% CI:1.42-2.58, p<0.01). 20 Conclusion: c-Met overexpression has correlation with poor prognosis of high grade 21 glioma patients.22

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Role and Therapeutic Targeting of the HGF/MET Pathway in Glioblastoma

Cited by 63 publications

References 90 publications

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma

Prognostic Role of c-Met Overexpression in High Grade Glioma: a Meta-analysis

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