Autonomous rhythmic activity in glioma networks drives brain tumour growth

Hausmann, David; Hoffmann, Dirk C.; Venkataramani, Varun; Jung, Eui-Man; Horschitz, Sandra; Tetzlaff, Svenja; Jabali, Ammar; Lü, Hai; Keßler, Tobias; Azorín, Daniel; Weil, Sophie; Kourtesakis, Alexandros; Sievers, Philipp; Habel, Antje; Breckwoldt, Michael O.; Karreman, Matthia A.; Ratliff, Miriam; Messmer, Julia M.; Yang, Yvonne; Reyhan, Ekin; Wendler, Susann; Löb, Cathrin; Mayer, Chanté D.; Figarella, Katherine; Osswald, Matthias; Solecki, Gergely; Sahm, Felix; Garaschuk, Olga; Kuner, Thomas; Koch, Philipp; Schlesner, Matthias; Wick, Wolfgang; Winkler, Frank

doi:10.1038/s41586-022-05520-4

Cited by 66 publications

(39 citation statements)

References 37 publications

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“…This modulation represents an example of cross-talk between two dominant signaling pathways in cells: Ca 2+ and cAMP. This mechanism may be particularly relevant in GBM, where several groups have demonstrated robust cytosolic Ca 2+ waves in tumor cells, which promote tumor growth (Hausmann et al, 2023; Venkataramani et al, 2019; Venkataramani et al, 2022; Venkatesh et al, 2019). We postulate that such waves boost GPR133 signaling in GBM cells by causing dissociation of ESYT1 from GPR133, a mechanism that may mediate some of the tumor-promoting effects of Ca 2+ waves and will require further testing.…”

Section: Discussionmentioning

confidence: 99%

Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1)

Stephan

Liu

Frenster

et al. 2023

Preprint

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GPR133 (ADGRD1) is an adhesion G protein-coupled receptor that signals through Gas and is required for growth of glioblastoma (GBM), an aggressive brain malignancy. The regulation of GPR133 signaling is incompletely understood. Here, we use proximity biotinylation proteomics to identify ESYT1, a Ca2+-dependent mediator of endoplasmic reticulum-plasma membrane bridge formation, as an intracellular interactor of GPR133. ESYT1 knockdown or knockout increases GPR133 signaling, while its overexpression has the opposite effect, without altering GPR133 levels in the plasma membrane. The GPR133-ESYT1 interaction requires the Ca2+-sensing C2C domain of ESYT1. Thapsigargin-mediated increases in cytosolic Ca2+ relieve signaling-suppressive effects of ESYT1 by promoting ESYT1-GPR133 dissociation. ESYT1 knockdown or knockout in GBM impairs tumor growth in vitro, suggesting functions of ESYT1 beyond the interaction with GPR133. Our findings suggest a novel mechanism for modulation of GPR133 signaling by increased cytosolic Ca2+, which reduces the signaling-suppressive interaction between GPR133 and ESYT1 to raise cAMP levels.

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Section: Discussionmentioning

confidence: 99%

Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1)

Stephan

Liu

Frenster

et al. 2023

Preprint

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“…IP inhibitors are frequently used as local anaesthetics, such as lidocaine and carbamazepine (7). We and others have uncovered the multifaceted roles of ion channels in regulating tumor cell-intrinsic properties and tumor cell-microenvironment interactions, thereby establishing specific ion channels as therapeutic targets in brain cancer (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Despite the identification of specific ion channels as regulators of malignancy of individual cancer types, a comprehensive interrogation of the transcriptomic landscape and clinical significance of the IP in human cancer has not been achieved.…”

Section: Introductionmentioning

confidence: 99%

Pan-cancer analysis of the ion permeome reveals functional regulators of glioblastoma aggression

Bahcheli

Min

Bayati

et al. 2023

Preprint

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Ion channels, transporters, and other ion-permeating proteins, collectively comprising the ion permeome (IP), are common drug targets. However, their roles in cancer are understudied. Our integrative pan-cancer analysis shows that IP genes display highly-elevated expression patterns in subsets of cancer samples significantly more often than expected transcriptome-wide. To enable target identification, we identified 410 survival-associated IP genes in 29 cancer types using a machine learning approach. Notably, GJB2 and SCN9A show prominent expression in neoplastic cells and associate with poor prognosis in glioblastoma (GBM), the most common and aggressive brain cancer. GJB2 or SCN9A knockdown in patient-derived GBM cells induces transcriptome-wide changes involving neural projection and proliferation pathways, impairs cell viability and tumor sphere formation, mitigates tunneling nanotube formation, and extends the survival of GBM-bearing mice. Thus, aberrant activation of IP genes appears as a pan-cancer feature of tumor heterogeneity that can be exploited for mechanistic insights and therapy development.

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“…Hausmann et al report that networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth 1,2 . Using inhibitors, Hausmann et al blocked the activity of the Ca 2+ activated potassium-channel protein KCa3.1 in in vitro models and mice, preventing proliferation of glioma cells and tumor expansion.…”

Section: Introductionmentioning

confidence: 99%

Increased KCNN4 expression related to poor survival in lower grade glioma

Lehrer

2023

Preprint

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Background Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of the Ca2+ activated potassium-channel protein KCa3.1 in in vitro models and mice, preventing proliferation of glioma cells and tumor expansion. Marked reduction of tumor cell viability occurred within the entire network, as well as reduced tumor growth in mice and extended animal survival. Methods KCa3.1 is encoded by the gene KCNN4 (Potassium Calcium-Activated Channel Subfamily N Member 4) on chromosome 19q13.31. We used the Cancer Genome Atlas (TCGA) to evaluate the effect of KCNN4 on human glioma survival in the TCGA Lower Grade Glioma (LGG) dataset. Results In humans KCNN4 is prognostic in glioma: high expression is unfavorable. In addition, KCNN4 copy number variations are prognostic. Increased masked copy number segments are unfavorable in lower grade glioma. KCNN4 is lost in gliomas with the 1p 19q codeletion, which may explain in part the comparatively favorable prognosis of 1p 19q codeletion tumors. Conclusion Our finding of increased KCNN4 expression related to poor survival in human lower grade glioma suggests that development of novel therapies, such as KCa3.1-inhibiting drugs, might be worthwhile.

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Autonomous rhythmic activity in glioma networks drives brain tumour growth

Cited by 66 publications

References 37 publications

Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1)

Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1)

Pan-cancer analysis of the ion permeome reveals functional regulators of glioblastoma aggression

Increased KCNN4 expression related to poor survival in lower grade glioma

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