Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer

Fung, Nok Him; Grima, Corrina; Widodo, Samuel S; Kaye, Andrew H.; Whitehead, Clarissa A.; Stylli, Stanley S.; Mantamadiotis, Theo

doi:10.1016/j.cellsig.2019.01.011

Cited by 12 publications

(4 citation statements)

References 81 publications

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“…As an initial experiment, we tested the two clinical compounds Mardepodect and Regorafenib in combination. Synergy between PI3K and cAMP signaling pathways has previously been suggested as potentially relevant in GBM [94]. We observed synergy in U87MG cells (with a maximum synergy score of 24), but modest antagonism between Mardepodect and Regorafenib in both T98G and A172 cells (with a maximum score of −21) (Figure 7).…”

Section: Combinations Of the Pde10a Inhibitor Mardepodect And Regorafenibsupporting

confidence: 56%

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Шаповалов¹,

Kopanitsa²,

Pruteanu³

et al. 2021

Cancers

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We have used three established human glioblastoma (GBM) cell lines—U87MG, A172, and T98G—as cellular systems to examine the plasticity of the drug-induced GBM cell phenotype, focusing on two clinical drugs, the phosphodiesterase PDE10A inhibitor Mardepodect and the multi-kinase inhibitor Regorafenib, using genome-wide drug-induced gene expression (DIGEX) to examine the drug response. Both drugs upregulate genes encoding specific growth factors, transcription factors, cellular signaling molecules, and cell surface proteins, while downregulating a broad range of targetable cell cycle and apoptosis-associated genes. A few upregulated genes encode therapeutic targets already addressed by FDA approved drugs, but the majority encode targets for which there are no approved drugs. Amongst the latter, we identify many novel druggable targets that could qualify for chemistry-led drug discovery campaigns. We also observe several highly upregulated transmembrane proteins suitable for combined drug, immunotherapy, and RNA vaccine approaches. DIGEX is a powerful way of visualizing the complex drug response networks emerging during GBM drug treatment, defining a phenotypic landscape which offers many new diagnostic and therapeutic opportunities. Nevertheless, the extreme heterogeneity we observe within drug-treated cells using this technique suggests that effective pan-GBM drug treatment will remain a significant challenge for many years to come.

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Section: Combinations Of the Pde10a Inhibitor Mardepodect And Regorafenibsupporting

confidence: 56%

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Шаповалов¹,

Kopanitsa²,

Pruteanu³

et al. 2021

Cancers

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“…Genomic and transcriptomic studies show that the PI3K and MAPK pathways are critical cell signaling pathways in GBM cell biology (Pearson and Regad 2017; P. M. Daniel, Filiz, Brown, et al 2018;Fung et al 2019). Our data identifies heterogeneous cell signaling activity across the GBM tumor microenvironment which correlates with histopathological hallmarks, including tumor cell density, angiogenesis and zones where tumor cell rich regions interface with the ECM-stroma (Figure S6).…”

Section: Discussionmentioning

confidence: 72%

Tissue remodeling and cell signaling underpin changes in tumor microenvironment heterogeneity in glioma oncogenesis

Dinevska

Widodo

Furst

et al. 2021

Preprint

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Brain tumor cells thrive by adapting to the signals in their microenvironment. Understanding how the tumor microenvironment evolves during disease progression is crucial to deciphering the mechanisms underlying the functional behavior of cancer cells. To adapt, cancer cells activate signaling and transcriptional programs and migrate to establish micro-niches, in response to signals from neighboring cells and non-cellular stromal factors. Using multiple tissue analysis approaches to identify and measure immune cell infiltration and extracellular matrix deposition in brain tumors, we show that low-grade glioma is largely devoid of infiltrating immune cells and extracellular matrix proteins, while high-grade glioma exhibits abundant immune cell infiltration and activation, as well as extensive collagen deposition. Spatial analysis shows that most T-cells are sequestered in perivascular nests, but macrophages penetrate deep into tumor cell rich regions. High-grade gliomas exhibit heterogeneous PI3K and MAPK signaling, which correlates with distinct pathological hallmarks, including tumor angiogenesis, tumor cell density and extracellular matrix deposition. Our results also provide compelling evidence that tissue remodeling is an important element in glioma progression, and that targeting the extracellular matrix will be critical to improving GBM therapy.

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“…were also upregulated in our study. These are key genes of pathways like PI3K signaling and JAK-STAT signaling and MAPK pathways are cross-linked with these pathways in various studies stating that activation of one pathway consequently leading to activation of the others 34,35 . All these results and information led us to the conclusion that MAPK pathway activation is the key oncogenic driver activated by chromosome 7 abnormalities and CLIP2-MET fusion in this GNT case.…”

Section: Discussionmentioning

confidence: 99%

A glioneuronal tumor with CLIP2-MET fusion

et al. 2020

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We report a case of glioneuronal tumor (GNT) with a discovery of novel gene fusion of CLIP2-MET resulting from aberrant chromosome 7 abnormalities. We executed an elaborate genomic study on this case including whole-exome sequencing and RNA sequencing. Genomic analysis of the tumor revealed aberrations in chromosomes 1 and 7 and a CLIP2-MET fusion. Further analysis of the upregulated genes revealed substantial connections with MAPK pathway activation. We concluded that the chromosome 7 abnormalities prompted CLIP2-MET gene fusion which successively leads to MAPK pathway activation. We deliberated that MAPK pathway activation is one of the driver pathways responsible for the oncogenesis of GNT.

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Understanding and exploiting cell signalling convergence nodes and pathway cross-talk in malignant brain cancer

Cited by 12 publications

References 81 publications

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Transcriptomics-Based Phenotypic Screening Supports Drug Discovery in Human Glioblastoma Cells

Tissue remodeling and cell signaling underpin changes in tumor microenvironment heterogeneity in glioma oncogenesis

A glioneuronal tumor with CLIP2-MET fusion

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