Publications
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Koch, Elise; Parker, Nadine; Mohammad, Helin; Lenk, Hasan Cagin; Ystaas, Lars Andreas Rømo & Jaholkowski, Piotr Pawel
[Show all 13 contributors for this article]
(2026).
Genetic overlap between treatment-resistant schizophrenia and smoking initiation.
International Journal of Neuropsychopharmacology.
ISSN 1461-1457.
29(7).
doi:
10.1093/ijnp/pyag035.
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Background
Early detection of treatment-resistant schizophrenia (TRS) is of substantial clinical importance. While TRS is heritable, the associated genetic variants have been difficult to identify. Cigarette smoking is associated with non-response to antipsychotics, and smoking behavior and schizophrenia have a shared genetic basis. Thus, TRS may also have a shared genetic basis with smoking behavior.
Objective
Here, we aim to identify genetic variants associated with TRS by leveraging overlapping genetic variants with smoking initiation to increase statistical power.
Methods
We analyzed genome-wide data for TRS and smoking initiation with the conditional/conjunctional false discovery rate (cond/conjFDR) to identify shared loci, and LD score regression to determine genetic correlations. To investigate potential causal effects of shared loci, we performed Mendelian randomization analyses. Shared loci were mapped to genes, which were further investigated for enrichment of drug target genes.
Results
We observed a significant positive genetic correlation between TRS and smoking initiation (rg = 0.47 P = .0002). Leveraging the genetic overlap between TRS and smoking initiation, we identified four novel loci jointly associated with TRS and smoking initiation. The condFDR results improved polygenic prediction of TRS. Mendelian randomization indicates putative evidence for a causal effect of genetic liability to TRS on smoking initiation. The functional genetic analyses suggest that alpha-1-adrenergic receptors may be involved in the pathophysiology of TRS and possibly related to the efficacy of clozapine versus other antipsychotic drugs.
Conclusion
In conclusion, our results show that shared genetic mechanisms influence both TRS and smoking behavior, which provide new insights into the biological underpinnings of TRS.
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Andersen, Johannes Kaasa; Ystaas, Lars Andreas Rømo; Bjerkvig, Rolf; Miletic, Hrvoje & Hossain, Md Jubayer al
(2026).
Tropism Profiling of Lentiviral Vector Pseudotypes in Diverse Brain Tumor Models.
Pharmaceutics.
18(1).
doi:
10.3390/pharmaceutics18010137.
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Background: Lentiviral vectors (LVs) show promise as gene therapy tools for brain tumors, but optimal envelope protein choices for different tumor types have not been determined. Methodology: This study evaluated three pseudotyped LV variants—VSV-GP, FuG-B2, and LCMV-GP—across diverse brain tumor cell lines including glioblastoma (GBM), diffuse intrinsic pontine glioma (DIPG), medulloblastoma, and metastatic brain cancers.
Results: VSV-GP and FuG-B2 pseudotypes significantly outperformed LCMV-GP across most tumor types. Both VSV-GP and FuG-B2 demonstrated high transduction efficiency in GBM and DIPG cells, though some cell lines displayed selective preferences for one pseudotype over the other. Medulloblastoma cells were challenging to transduce, with only VSV-GP achieving substantial efficacy. Metastatic brain cancers showed distinct tropism patterns: melanoma metastases were preferentially transduced by the FuG-B2 pseudotype, while lung metastases showed preference for the VSV-GP pseudotype.
Conclusions: These findings suggest envelope protein selection should be tailored to specific brain tumor types. VSV-GP appears most suitable for medulloblastoma and lung metastases, FuG-B2 for melanoma metastases, and both for GBM and DIPG gene therapy applications. The study provides crucial guidance for translating lentiviral gene therapy to clinical applications, supporting personalized treatment strategies based on tumor-specific vector tropism profiles.
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Solel, Ege; Brudvik, Egil; Ystaas, Lars Andreas Rømo; Yabo, Yahaya A.; Rigg, Emma & Choudhury, Romi Roy
[Show all 11 contributors for this article]
(2025).
Gasdermin E in glioblastoma –pyroptosis resistance and tumor-promoting functions.
Cell death discovery.
11.
doi:
10.1038/s41420-025-02572-z.
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Treatment of glioblastoma (GB), the most common and most aggressive malignant brain tumor, has made little progress over the past two decades. Despite extensive research on apoptosis and autophagy, necrotic cell death mechanisms like pyroptosis, which have the potential to stimulate anti-tumor immune responses, remain largely underexplored in GB. Here, we investigated whether Gasdermin E (GSDME)-mediated pyroptosis can be induced in GB by employing the drug raptinal, an inducer of cytochrome c release. Using human patient-derived and mouse GB cell lines, we showed that raptinal promotes GSMDE cleavage. However, although a strong pyroptotic response was observed in mouse cell lines, it was weak in human cell lines. This resistance was partially reversed by the calcium chelator BAPTA-AM, indicating that membrane repair mechanisms may counteract the pyroptotic response. Gsdme knockout (KO) in mouse GB cells unexpectedly prolonged the survival of immunocompetent mice, demonstrating a tumor-promoting role of GSDME independent of its pyroptotic function. Analysis of the immune microenvironment revealed that Gsdme KO promoted infiltration of T cells, which was confirmed by spatial transcriptomic analysis of GB patient samples. In addition, Gsdme/GSMDE KO reduced the invasive capacity of mouse/human GB cells. In conclusion, active membrane repair mechanisms may impair the pyroptotic efficacy in GB. GSDME has a tumor-promoting role in GB by suppressing T cell infiltration and increasing tumor cell invasion.
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Watson, Dionysios C.; Bayik, Defne; Storevik, Simon Humberto; Moreino, Shannon Sherwin; Sprowls, Samuel A. & Han, Jianhua
[Show all 42 contributors for this article]
(2023).
GAP43-dependent mitochondria transfer from astrocytes enhances glioblastoma tumorigenicity.
Nature Cancer.
4,
p. 648–664.
doi:
10.1038/s43018-023-00556-5.
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The transfer of intact mitochondria between heterogeneous cell types has been confirmed in various settings, including cancer. However, the functional implications of mitochondria transfer on tumor biology are poorly understood. Here we show that mitochondria transfer is a prevalent phenomenon in glioblastoma (GBM), the most frequent and malignant primary brain tumor. We identified horizontal mitochondria transfer from astrocytes as a mechanism that enhances tumorigenesis in GBM. This transfer is dependent on network-forming intercellular connections between GBM cells and astrocytes, which are facilitated by growth-associated protein 43 (GAP43), a protein involved in neuron axon regeneration and astrocyte reactivity. The acquisition of astrocyte mitochondria drives an increase in mitochondrial respiration and upregulation of metabolic pathways linked to proliferation and tumorigenicity. Functionally, uptake of astrocyte mitochondria promotes cell cycle progression to proliferative G2/M phases and enhances self-renewal and tumorigenicity of GBM. Collectively, our findings reveal a host–tumor interaction that drives proliferation and self-renewal of cancer cells, providing opportunities for therapeutic development.
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Rigg, Emma Kayleigh; Wang, Jiwei; Xue, Zhiwei; Lunavat, Taral; Liu, Guowei & Hoang, Tuyen
[Show all 20 contributors for this article]
(2023).
Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.
Journal of Extracellular Vesicles.
12(10).
doi:
10.1002/jev2.12363.
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Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.
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Ferreira, Tiago; Kulkarni, Amit; Bretscher, Clemens; Nazarov, Petr V.; Hossain, Md Jubayer al & Ystaas, Lars Andreas Rømo
[Show all 10 contributors for this article]
(2022).
Oncolytic H-1 Parvovirus Hijacks Galectin-1 to Enter Cancer Cells.
Viruses.
14(5).
doi:
10.3390/v14051018.
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Clinical studies in glioblastoma and pancreatic carcinoma patients strongly support the further development of H-1 protoparvovirus (H-1PV)-based anticancer therapies. The identification of cellular factors involved in the H-1PV life cycle may provide the knowledge to improve H-1PV anticancer potential. Recently, we showed that sialylated laminins mediate H-1PV attachment at the cell membrane. In this study, we revealed that H-1PV also interacts at the cell surface with galectin-1 and uses this glycoprotein to enter cancer cells. Indeed, knockdown/out of LGALS1, the gene encoding galectin-1, strongly decreases the ability of H-1PV to infect and kill cancer cells. This ability is rescued by the re-introduction of LGALS1 into cancer cells. Pre-treatment with lactose, which is able to bind to galectins and modulate their cellular functions, decreased H-1PV infectivity in a dose dependent manner. In silico analysis reveals that LGALS1 is overexpressed in various tumours including glioblastoma and pancreatic carcinoma. We show by immunohistochemistry analysis of 122 glioblastoma biopsies that galectin-1 protein levels vary between tumours, with levels in recurrent glioblastoma higher than those in primary tumours or normal tissues. We also find a direct correlation between LGALS1 transcript levels and H-1PV oncolytic activity in 53 cancer cell lines from different tumour origins. Strikingly, the addition of purified galectin-1 sensitises poorly susceptible GBM cell lines to H-1PV killing activity by rescuing cell entry. Together, these findings demonstrate that galectin-1 is a crucial determinant of the H-1PV life cycle.
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Kulkarni, Amit; Ferreira, Tiago; Bretscher, Clemens; Grewenig, Annabel; El-Andaloussi, Nazim & Bonifati, Serena
[Show all 19 contributors for this article]
(2021).
Oncolytic H-1 parvovirus binds to sialic acid on laminins for cell attachment and entry.
Nature Communications.
12(1).
doi:
10.1038/s41467-021-24034-7.
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H-1 parvovirus (H-1PV) is a promising anticancer therapy. However, in-depth understanding of its life cycle, including the host cell factors needed for infectivity and oncolysis, is lacking. This understanding may guide the rational design of combination strategies, aid development of more effective viruses, and help identify biomarkers of susceptibility to H-1PV treatment. To identify the host cell factors involved, we carry out siRNA library screening using a druggable genome library. We identify one crucial modulator of H-1PV infection: laminin γ1 (LAMC1). Using loss- and gain-of-function studies, competition experiments, and ELISA, we validate LAMC1 and laminin family members as being essential to H-1PV cell attachment and entry. H-1PV binding to laminins is dependent on their sialic acid moieties and is inhibited by heparin. We show that laminins are differentially expressed in various tumour entities, including glioblastoma. We confirm the expression pattern of laminin γ1 in glioblastoma biopsies by immunohistochemistry. We also provide evidence of a direct correlation between LAMC1 expression levels and H-1PV oncolytic activity in 59 cancer cell lines and in 3D organotypic spheroid cultures with different sensitivities to H-1PV infection. These results support the idea that tumours with elevated levels of γ1 containing laminins are more susceptible to H-1PV-based therapies.
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Hossain, Jubayer; Latif, Md Abdul; Ystaas, Lars Andreas Rømo; Ninzima, Sandra; Riecken, Kristoffer & Muller, Arnaud
[Show all 13 contributors for this article]
(2019).
Long-term treatment with valganciclovir improves lentiviral suicide gene therapy of glioblastoma.
Neuro-Oncology.
ISSN 1522-8517.
21(7),
p. 890–900.
doi:
10.1093/neuonc/noz060.
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Background: Suicide gene therapy for malignant gliomas has shown encouraging results in the latest clinical trials. However, prodrug application was most often restricted to short-term treatment (14 days), especially when replication-defective vectors were used. We previously showed that a substantial fraction of herpes simplex virus thymidine kinase (HSV-TK) transduced tumor cells survive ganciclovir (GCV) treatment in an orthotopic glioblastoma (GBM) xenograft model. Here we analyzed whether these TK+ tumor cells are still sensitive to prodrug treatment and whether prolonged prodrug treatment can enhance treatment efficacy. Methods: Glioma cells positive for TK and green fluorescent protein (GFP) were sorted from xenograft tumors recurring after suicide gene therapy, and their sensitivity to GCV was tested in vitro. GBM xenografts were treated with HSV-TK/GCV, HSV-TK/valganciclovir (valGCV), or HSV-TK/valGCV + erlotinib. Tumor growth was analyzed by MRI, and survival as well as morphological and molecular changes were assessed. Results: TK-GFP+ tumor cells from recurrent xenograft tumors retained sensitivity to GCV in vitro. Importantly, a prolonged period (3 mo) of prodrug administration with valganciclovir (valGCV) resulted in a significant survival advantage compared with short-term (3 wk) application of GCV. Recurrent tumors from the treatment groups were more invasive and less angiogenic compared with primary tumors and showed significant upregulation of epidermal growth factor receptor (EGFR) expression. However, double treatment with the EGFR inhibitor erlotinib did not increase therapeutic efficacy. Conclusion: Long-term treatment with valGCV should be considered as a replacement for short-term treatment with GCV in clinical trials of HSV-TK mediated suicide gene therapy.
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Published
Dec. 5, 2023 1:38 PM
- Last modified
Dec. 5, 2023 1:38 PM
