Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Kegelman, Timothy P.; Wu, Bainan; Das, Swadesh K.; Talukdar, Sarmistha; Beckta, Jason M.; Hu, Bin; Emdad, Luni; Valerie, Kristoffer; Sarkar, Devanand; Furnari, Frank B.; Cavenee, Webster K.; Wei, Jun; Purves, Angela; De, Surya K.; Pellecchia, Maurizio; Fisher, Paul B.

doi:10.1073/pnas.1616100114

Cited by 89 publications

(133 citation statements)

References 49 publications

(73 reference statements)

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“…Given that integrins play a crucial role in brain tumor infiltration 42 and GBM intratumor variability in integrin expressions 43 . New trials that aim to halt GBM recurrence by inhibiting radiation-induced invasion gains and signaling changes 11,44 , or kinase inhibitors 10 , could benefit from accounting for intra-and-intertumoral differences in single cell migration. Boxplots show spatial and intertumoral heterogeneity in cell area and cell elongation.…”

Section: Discussionmentioning

confidence: 99%

Spatial heterogeneity of cell-matrix adhesive forces predicts human glioblastoma migration

Rezk¹,

Jia²,

Wendler³

et al. 2020

Preprint

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Key pointsGBM tumors are biomechanically heterogeneous GBM cell migration is inversely correlated with cell-matrix adhesion strength 5-ALA fluorescence intensity during surgery correlates with the motility properties of GBM cells Importance of the studyThis is the first study to compare single cell migration and cell-matrix adhesion strength of GBM, using cell lines derived from different tumors and from different regions within the same tumor. Not accounting for internal sampling location within each tumor obscures differences in cell morphology, motility and adhesion properties between patients. Peripherical and marginal tumor cells have different adhesion profiles and are highly migratory compared to those found in the core of the tumor. Aggressive regions of the tumor (highly motile) are linked to the spatial distribution of adhesion strength and are strongly associated with 5-ALA fluorescence intensity. Preclinical tests aimed at developing a treatment for GBM using anti-invasive drugs or adhesion inhibitors, would benefit from using cell lines derived from the tumor periphery (with low 5-ALA intensity) rather than cell lines derived from the tumor core.

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Section: Discussionmentioning

confidence: 99%

Spatial heterogeneity of cell-matrix adhesive forces predicts human glioblastoma migration

Rezk¹,

Jia²,

Wendler³

et al. 2020

Preprint

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“…The combination of 113B7 with radiotherapy produced significant effects in decreasing GBM invasion and enhanced survival. Together, these data suggest that an effective PDZ inhibitor can complement traditional radiotherapy to combat aggressive cancers, such as GBM (Kegelman et al, 2017).…”

Section: Pdz Domain Inhibitors In Cancermentioning

confidence: 84%

“…However, targeting lager fragments containing multiple PDZ domains, rather than an isolated PDZ domain, might provide the required specificity. Syntenin is a good example of this, where the 113B7 inhibitor targeted PDZ1 and the linker between PDZ1 and PDZ2, but not PDZ2 (Kegelman et al, 2017). This example suggests that the interfaces between PDZ domains and their adjacent domains might provide greater specificity than the isolated PDZ domain.…”

Section: Pdz Domain Inhibitors In Cystic Fibrosismentioning

confidence: 99%

Emerging Themes in PDZ Domain Signaling

Liu

Fuentes

2019

International Review of Cell and Molecular Biology

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Post-synaptic density-95, disks-large and zonula occludens-1 (PDZ) domains are small globular proteineprotein interaction domains widely conserved from yeast to humans. They are composed of w90 amino acids and form a classical two a-helical/six b-strand structure. The prototypical ligand is the C-terminus of partner proteins; however, they also bind internal peptide sequences. Recent findings indicate that PDZ domains also bind phosphatidylinositides and cholesterol. Through their ligand interactions, PDZ domain proteins are critical for cellular trafficking and the surface retention of various ion channels. In addition, PDZ proteins are essential for neuronal signaling, memory, and learning. PDZ proteins also contribute to cytoskeletal dynamics by mediating interactions critical for maintaining cellecell junctions, cell polarity, and cell migration. Given their important biological roles, it is not surprising that their dysfunction can lead to multiple disease states. As such, PDZ domainecontaining proteins have emerged as potential targets for the development of small molecular inhibitors as therapeutic agents. Recent data suggest that the critical binding function of PDZ domains in cell signaling is more than just glue, and their binding function can be regulated by phosphorylation or allosterically by other binding partners. These studies also provide a wealth of structural and biophysical data that are beginning to reveal the physical features that endow this small modular domain with a central role in cell signaling.

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“…An interesting possibility for inhibiting the NF-κB pathway in conjunction with proteasome inhibition is through inhibition of MDA-9/Syntenin, which has shown promise in preclinical studies in reducing the invasiveness of radiation-induced GBM in adults. 44 Targeting the MAPK pathway may also be an effective strategy given the frequent NF1 mutations in TIHGG; MEK inhibition is a therapeutic strategy of interest in HGG and was effective (trametinib) in both TIHGG derived cell lines 45, 46 .…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets

DeSisto

Lucas

et al. 2019

Preprint

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Author Contributions 25ALG and JTL conceived the project and overall experimental design. AD assisted with sample 26 processing and data analysis. JTL and CH designed and analyzed de novo pHGG and TIHGG imaging data. 27 ALG and JTL compiled and analyzed TIHGG clinical and imaging data; LH and AL performed analysis of 28 radiation treatment for the Colorado cohort. MH and TCH procured tumor samples. US provided 29 methylation profiling data and clinical information for tumor samples. SA processed samples and 30 performed fluorescence in situ hybridization. TL, QT, and BAO analyzed 450/850K data from TIHGG 31 and pHGG cases. JTL, KX, GW, and BAO conceived of the relevant comparisons to de novo pHGG copy-32 number and sequencing data. JD, BS, KJ, and ALG designed the relevant comparisons and performed 33 analyses of germline and somatic sequencing data, RNA-seq data, drug screening results. SJB provided 34 DNA methylation and sequencing data from PCGP cases with a history of therapeutic ionizing radiation. 35 JD performed all primary cell line experiments, assisted by PF and RL. LMH, KD, JML, NF, and RV assisted 36 with project planning and data analysis. GW, KX, KJ, and DH, performed all computational analyses and 37 interpretation of the germline and somatic sequencing data. JTL, JD, and KX performed statistical 38 analyses. MA, GA, BAO, NF, and SB contributed primary tumor samples and clinical data. KX completed 39 the reconstruction of episomes from WGS data. JTL, AG, BAO, TL, JD, KX, QT and GW contributed to the 40 interpretation of experiments. JTL and JD wrote the manuscript with input from all co-authors; all 41 coauthors were involved with manuscript revision, which was led by JTL, JD, BAO, and ALG. 42 Acknowledgements 43 We thank members of the Zhang and Wu laboratories (St. Jude Children's Research Hospital) 44 and members of the Foreman and Vibhakar laboratories (University of Colorado) for assistance and 45 discussion. We also thank Matthew Lear (St. Jude Children's Research Hospital) for his help in acquiring 46 and performing preliminary clinical analysis of primary tumor samples and Scott Olsen, Granger Ridout, 47 and Emily Walker (Hartwell Center for Bioinformatics and Biotechnology) for their assistance in 48 sequencing samples. RNA-seq library preparation and high-throughput sequencing were conducted at 49

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Inhibition of radiation-induced glioblastoma invasion by genetic and pharmacological targeting of MDA-9/Syntenin

Cited by 89 publications

References 49 publications

Spatial heterogeneity of cell-matrix adhesive forces predicts human glioblastoma migration

Spatial heterogeneity of cell-matrix adhesive forces predicts human glioblastoma migration

Emerging Themes in PDZ Domain Signaling

Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets

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