Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

Scheer, Maximilian; Leisz, Sandra; Sorge, Eberhard; Storozhuk, Olha; Prell, Julian; Ho, Ivy A. W.; Harder, Anja

doi:10.3390/ijms23010352

Cited by 10 publications

(6 citation statements)

References 139 publications

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“…In our experimental model, we did not force any oncogenic expression of active RAS, and RAS is not mutated in the glioblastoma cells used [18], in line with the low frequency of H-RAS, K-RAS and N-RAS mutations in glioblastoma patients [36,37]. Interestingly, macropinocytosis-proficient U373-MG cells harbour frameshift indels in the NF1 gene [18], and mutations or deletions in NF1 are typical genetic abnormalities occurring in the transition from the proneural to the mesenchymal subtype of glioblastoma, which has the most aggressive malignant behaviour [38]. The protein encoded by NF1, neurofibromin-1, is a GTPase-activating protein (GAP) that negatively regulates the activity of multiple members of the RAS family by accelerating the hydrolysis of active GTP-RAS [39].…”

Section: Discussionmentioning

confidence: 64%

The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells

et al. 2022

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Background Glioblastoma is a highly aggressive brain tumor. A big effort is required to find novel molecules which can cross the blood–brain barrier and efficiently kill these tumor cells. In this perspective, trehalose (α-glucopyranosyl‐[1→1]‐α‐d‐glucopyranoside), found in various dietary sources and used as a safe nutrient supplement, attracted our attention for its pleiotropic effects against tumor cells. Methods Human glioblastoma cell lines U373-MG and T98G were exposed to trehalose and analyzed at different time points. Cell proliferation was evaluated at medium term, and clonogenic capacity and cell morphology were evaluated at long term. Western blot was used to evaluate biochemical markers of autophagy (also measured in cells co-treated with EIPA or chloroquine), and mTOR, AMPK and ERK 1/2 signalling. Macropinocytosis was evaluated morphologically by bright-field microscopy; in cells loaded with the fluorescein-conjugated fluid-phase tracer dextran, macropinocytic vacuoles were also visualized by fluorescence microscopy, and the extent of macropinocytosis was quantified by flow cytometry. Results The long-term effect of trehalose on U373-MG and T98G cell lines was impressive, as indicated by a dramatic reduction in clonogenic efficiency. Mechanistically, trehalose proved to be an efficient autophagy inducer in macropinocytosis-deficient T98G cells and an efficient inducer of macropinocytosis and eventual cell death by methuosis in U373-MG glioblastoma cells, proved to be poorly responsive to induction of autophagy. These two processes appeared to act in a mutually exclusive manner; indeed, co-treatment of U373-MG cells with the macropinocytosis inhibitor, EIPA, significantly increased the autophagic response. mTOR activation and AMPK inhibition occurred in a similar way in the two trehalose-treated cell lines. Interestingly, ERK 1/2 was activated only in macropinocytosis-proficient U373-MG cells harbouring loss-of-function mutations in the negative RAS regulator, NF1, suggesting a key role of RAS signalling. Conclusions Our results indicate that trehalose is worthy of further study as a candidate molecule for glioblastoma therapy, due to its capacity to induce a sustained autophagic response, ultimately leading to loss of clonogenic potential, and more interestingly, to force macropinocytosis, eventually leading to cell death by methuosis, particularly in tumor cells with RAS hyperactivity. As a further anticancer strategy, stimulation of macropinocytosis may be exploited to increase intracellular delivery of anticancer drugs.

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Section: Discussionmentioning

confidence: 64%

The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells

et al. 2022

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“…In fact, we detected three immunogenic neoepitopes from patient NVB05 derived from a frameshift mutation in NF1. Mutations in the NF1 gene has been reported in 13-14% of GBM, hereof 78% consisting of frameshifts 47 . Additionally, NF1 mutations has been described to be related to high T-cell infiltration in gliomas 48 .…”

Section: Discussionmentioning

confidence: 99%

Altered intratumoral immune composition after Nivolumab treatment in patients with recurrent glioblastoma

Hadrup,

Skadborg,

Maarup

et al. 2023

Preprint

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Glioblastoma is an aggressive brain tumor with poor prognosis, and consequently immunotherapy is being explored as a potential treatment option. However, it is unclear whether systemic immunotherapy can reach and modify the tumor microenvironment in the brain. We evaluated immune characteristics in tumor and blood samples from recurrent glioblastoma patients, who received Nivolumab and Bevacizumab. One group received Nivolumab one week prior to surgery, and immune characteristics of the tumor were compared to control patients receiving salvage resection without prior Nivolumab treatment. Nivolumab-bound T-cells could be detected in tumor tissue, along with increasing numbers of both activated and differentiated CD4+ and CD8+ T-cells. An associated upregulation of co-inhibitory receptors on T-cells was observed following Nivolumab treatment. Additionally, tumor-reactivity was detected in tumor infiltrating lymphocytes (TILs) from Nivolumab-treated patients, and neoantigen-reactive T-cells could be identified in both TILs and blood, indicating a systemic response towards GBM in a subset of patients.

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“…This is associated with an immune signature and mediated via the NF1–MAPK–FOSL1 axis. (Scheer et al, 2022).…”

Section: Introductionmentioning

confidence: 98%

“…role in inducing the mesenchymal (MES) subtype and, therefore, defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1-MAPK-FOSL1 axis (Scheer et al, 2022)…”

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confidence: 99%

A review of natural products and small‐molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges

Pasdaran,

Grice,

Hamedi

2024

Drug Development Research

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In 2021, the World Health Organization released the fifth edition of the central nervous system (CNS) tumor classification. This classification uses histopathology and molecular pathogenesis to group tumors into more biologically and molecularly defined entities. The prognosis of brain cancer, particularly malignant tumors, has remained poor worldwide, approximately 308,102 new cases of brain and other CNS tumors were diagnosed in the year 2020, with an estimated 251,329 deaths. The cost and time‐consuming nature of studies to find new anticancer agents makes it necessary to have well‐designed studies. In the present study, the pathways that can be targeted for drug development are discussed in detail. Some of the important cellular origins, signaling, and pathways involved in the efficacy of bioactive molecules against CNS tumorigenesis or progression, as well as prognosis and common approaches for treatment of different types of brain tumors, are reviewed. Moreover, different study tools, including cell lines, in vitro, in vivo, and clinical trial challenges, are discussed. In addition, in this article, natural products as one of the most important sources for finding new chemotherapeutics were reviewed and over 700 reported molecules with efficacy against CNS cancer cells are gathered and classified according to their structure. Based on the clinical trials that have been registered, very few of these natural or semi‐synthetic derivatives have been studied in humans. The review can help researchers understand the involved mechanisms and design new goal‐oriented studies for drug development against CNS malignancies.

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Neurofibromatosis Type 1 Gene Alterations Define Specific Features of a Subset of Glioblastomas

Cited by 10 publications

References 139 publications

The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells

The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells

Altered intratumoral immune composition after Nivolumab treatment in patients with recurrent glioblastoma

A review of natural products and small‐molecule therapeutics acting on central nervous system malignancies: Approaches for drug development, targeting pathways, clinical trials, and challenges

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