Vesicle Cholesterol Controls Exocytotic Fusion Pore

Rituper, Boštjan; Guček, Alenka; Lisjak, Marjeta; Górska, Urszula; Šakanović, Aleksandra; Bobnar, Saša Trkov; Lasič, Eva; Božić, Mićo; Abbineni, Prabhodh S.; Jorgačevski, Jernej; Kreft, Marko; Verkhratsky, Alexei; Platt, Frances M.; Anderluh, Gregor; Stenovec, Matjaž; Božić, Bojan; Coorssen, Jens R.; Zorec, Robert

doi:10.2139/ssrn.3827407

Cited by 2 publications

(2 citation statements)

References 98 publications

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“…Cholesterol plays a critical role in vesicular trafficking [111] by affecting membrane fusion [112]. A whole-cell membrane capacitance measurement showed that extraction of cholesterol caused impaired vesicular endocytosis [113] and exocytosis by controlling the fusion pore conductance [114]. On the other hand, cellular cholesterol level is regulated by endocytosis of cellular cholesterol content to lysosomes [115], where cholesterol induces the activation of mTOR [116, 117], a known regulator of cell translation and proliferation [118, 119].…”

Section: Discussionmentioning

confidence: 99%

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Shojaei

Amereh²,

Alizadeh

et al. 2022

Preprint

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Chemoresistance is a major clinical challenge in the management of glioblastoma (GBM) Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that the acquisition of resistance increases invasiveness and the presence of neurons decreases this property.

show abstract

Section: Discussionmentioning

confidence: 99%

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Shojaei

Amereh²,

Alizadeh

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…A whole-cell membrane capacitance measurement showed that extraction of cholesterol caused impaired vesicular endocytosis [113] and exocytosis by controlling the fusion pore conductance [114]. On the other hand, cellular cholesterol level is regulated by endocytosis of cellular cholesterol content to lysosomes [115], where cholesterol induces the activation of mTOR [116,117], a known regulator of cell translation and proliferation [118,119].…”

Section: Discussionmentioning

confidence: 99%

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

Shojaei

Amereh

Alizadeh

et al. 2022

Preprint

View full text Add to dashboard Cite

Chemoresistance is a major clinical challenge in management of glioblastoma (GBM). Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that acquisition of resistance increases invasiveness and the presence of neurons decreases this property.

show abstract

Vesicle Cholesterol Controls Exocytotic Fusion Pore

Cited by 2 publications

References 98 publications

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma

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