bims-malgli 2020-08-30 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2020–08–30
seven papers selected by
Oltea Sampetrean, Keio University

TRPV4 activates the Cdc42/N-wasp pathway to promote glioblastoma invasion by altering cellular protrusions.
Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.
Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma.
Epidermal Growth Factor Receptor (EGFR) as a molecular determinant of glioblastoma response to dopamine receptor 2 (DRD2) inhibitors.
Evidence for hypoxia increasing the tempo of evolution in glioblastoma.
PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models.
Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients.

Sci Rep. 2020 Aug 25. 10(1): 14151

TRPV4 activates the Cdc42/N-wasp pathway to promote glioblastoma invasion by altering cellular protrusions.

Wei Yang, Peng-Fei Wu, Jian-Xing Ma, Mao-Jun Liao, Lun-Shan Xu, Liang Yi.

The invasion ability of glioblastoma (GBM) causes tumor cells to infiltrate the surrounding brain parenchyma and leads to poor outcomes. Transient receptor potential vanilloid 4 (TRPV4) exhibits a remarkable role in cancer cell motility, but the contribution of TRPV4 to glioblastoma metastasis is not fully understood. Here, we reported that TRPV4 expression was significantly elevated in malignant glioma compared to normal brain and low-grade glioma, and TRPV4 expression was negatively correlated with the prognosis of glioma patients. Functionally, stimulation of TRPV4 promoted glioblastoma cell migration and invasion, and repression of TRPV4 hindered the migration and invasion of glioblastoma cells in vitro. Molecularly, TRPV4 strongly colocalized and interacted with skeletal protein-F-actin at cellular protrusions, and TRPV4 regulated the formation of invadopodia and filopodia in glioblastoma cells. Furthermore, the Cdc42/N-wasp axis mediated the effect of TRPV4-regulated cellular protrusions and invasion. Foremost, TRPV4 inhibitor treatment or downregulation of TRPV4 significantly reduced the invasion-growth of subcutaneously and intracranially transplanted glioblastoma in mice. In conclusion, the TRPV4/Cdc42/wasp signaling axis regulates cellular protrusion formation in glioblastoma cells and influences the invasion-growth phenotype of glioblastoma in vivo. TRPV4 may serve as a prognostic factor and specific therapeutic target for GBM patients.

DOI: https://doi.org/10.1038/s41598-020-70822-4
Genome Biol. 2020 Aug 26. 21(1): 216

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma.

Jason K Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho, Michele Ceccarelli, Luigi Cerulo, Jinlong Yin, Sung Soo Kim, Francesca P Caruso, Mijeong Lee, Donggeon Kim, Young Taek Oh, Yeri Lee, Nam-Gu Her, Byeongkwi Min, Hye-Jin Kim, Da Eun Jeong, Hye-Mi Kim, Hyunho Kim, Seok Chung, Hyun Goo Woo, Jeongwu Lee, Doo-Sik Kong, Ho Jun Seol, Jung-Il Lee, Jinho Kim, Woong-Yang Park, Qianghu Wang, Erik P Sulman, Amy B Heimberger, Michael Lim, Jong Bae Park, Antonio Iavarone, Roel G W Verhaak, Do-Hyun Nam.

BACKGROUND: Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.
RESULTS: We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.
CONCLUSIONS: Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

DOI: https://doi.org/10.1186/s13059-020-02140-x
Oncogene. 2020 Aug 27.

Isocitrate dehydrogenase 1 mutation enhances 24(S)-hydroxycholesterol production and alters cholesterol homeostasis in glioma.

Risheng Yang, Yuanlin Zhao, Yu Gu, Ying Yang, Xing Gao, Yuan Yuan, Liming Xiao, Jin Zhang, Chao Sun, Han Yang, Junhui Qin, Jing Li, Feng Zhang, Lijun Zhang, Jing Ye.

Isocitrate dehydrogenase (IDH) mutation is the most important initiating event in gliomagenesis, and the increasing evidence shows that IDH mutation is associated with the metabolic reprogramming in the tumor. Dysregulated cholesterol metabolism is a hallmark of tumor cells, but the cholesterol homeostasis in IDH-mutated glioma is still unknown. In this study, we found that astrocyte-specific mutant IDH1(R132H) knockin reduced the cholesterol contents and damaged the structure of myelin in mouse brains. In U87 and U251 cells, the expression of mutant IDH1 consistently reduced the cholesterol levels. Furthermore, we found that IDH1 mutation enhanced the production of 24(S)-hydroxycholesterol (24-OHC), which is not only the metabolite of cholesterol elimination, but also functions as an endogenous ligand for the liver X receptors (LXRs). In IDH1-mutant glioma cells, the elevated 24-OHC activated LXRs, which consequently accelerated the low-density lipoprotein receptor (LDLR) degradation by upregulating the inducible degrader of the LDLR (IDOL). The reduced LDLR expressions in IDH1-mutant glioma cells abated the uptakes of low-density lipoprotein (LDL) to decrease the cholesterol influx. In addition, the activated LXRs also promoted the cholesterol efflux by elevating the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and apolipoprotein E (ApoE) in both IDH1-mutant astrocytes and glioma cells. As a feedback, the reduced cholesterol levels stimulated the cholesterol biosynthesis, which made IDH1-mutated glioma cells more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase. The altered cholesterol homeostasis regulated by mutant IDH provides a pivotal therapeutical strategy for the IDH-mutated gliomas.

DOI: https://doi.org/10.1038/s41388-020-01439-0
Neuro Oncol. 2020 Aug 24. pii: noaa188. [Epub ahead of print]

Epidermal Growth Factor Receptor (EGFR) as a molecular determinant of glioblastoma response to dopamine receptor 2 (DRD2) inhibitors.

Yuyu He, Jie Li, Tomoyuki Koga, Jun Ma, Sanjay Dhawan, Yuta Suzuki, Frank Furnari, Varun V Prabhu, Joshua E Allen, Clark C Chen.

   BACKGROUND: There are ongoing clinical trials exploring the efficacy of dopamine receptor 2 (DRD2) inhibition against glioblastomas, the most common primary brain tumor. Here we examine potential molecular determinants of this efficacy.
METHODS: The Cancer Genome Atlas (TCGA) glioblastoma database and other published mRNA profiles were used to analyze the DRD2 and EGFR expression pattern. In vitro and in vivo responses to DRD2 inhibitors were determined using patient derived xenograft (PDX) glioblastoma models. Immunohistochemical studies were performed on clinically annotated glioblastoma samples derived from patients treated with ONC201.
RESULTS: Analysis of clinical glioblastoma specimens derived from independent patient cohorts revealed an inverse correlation between EGFR and DRD2 mRNA expression, with implication that signaling mediated by these proteins shares overlapping functions. In independent panels of PDX glioblastoma lines, high EGFR expression was associated with poor in vitro and in vivo response to DRD2 inhibitors, including haloperidol and ONC201. Moreover, ectopic expression of a constitutively active EGFR, EGFRvIII, suppressed glioblastoma sensitivity to ONC201. DRD2 expression positively correlated with expression of rate-limiting enzymes for dopamine synthesis as well as dopamine secretion, suggesting contribution of autocrine DRD2 signaling. Analysis of specimens from patients treated with ONC201 (n = 15) showed an inverse correlation between the intensity of EGFR staining and clinical response. The median overall survival for patients with high and low EGFR staining was 162 and 373 days, respectively (p = 0.037).
CONCLUSIONS: High EGFR expression is a determinant of poor glioblastoma response to DRD2. This finding should inform future clinical trial designs.

Keywords:  DRD2; EGFR; ONC201; anti-DRD2 treatment; efficacy

DOI:  https://doi.org/10.1093/neuonc/noaa188
Br J Cancer. 2020 Aug 27.

Evidence for hypoxia increasing the tempo of evolution in glioblastoma.

David Robert Grimes, Marnix Jansen, Robert J Macauley, Jacob G Scott, David Basanta.

BACKGROUND: Tumour hypoxia is associated with metastatic disease, and while there have been many mechanisms proposed for why tumour hypoxia is associated with metastatic disease, it remains unclear whether one precise mechanism is the key reason or several in concert. Somatic evolution drives cancer progression and treatment resistance, fuelled not only by genetic and epigenetic mutation but also by selection from interactions between tumour cells, normal cells and physical micro-environment. Ecological habitats influence evolutionary dynamics, but the impact on tempo of evolution is less clear.
METHODS: We explored this complex dialogue with a combined clinical-theoretical approach by simulating a proliferative hierarchy under heterogeneous oxygen availability with an agent-based model. Predictions were compared against histology samples taken from glioblastoma patients, stained to elucidate areas of necrosis and TP53 expression heterogeneity.
RESULTS: Results indicate that cell division in hypoxic environments is effectively upregulated, with low-oxygen niches providing avenues for tumour cells to spread. Analysis of human data indicates that cell division is not decreased under hypoxia, consistent with our results.
CONCLUSIONS: Our results suggest that hypoxia could be a crucible that effectively warps evolutionary velocity, making key mutations more likely. Thus, key tumour ecological niches such as hypoxic regions may alter the evolutionary tempo, driving mutations fuelling tumour heterogeneity.

DOI: https://doi.org/10.1038/s41416-020-1021-5
Sci Adv. 2020 Jul;6(30): eabb4105

PET, image-guided HDAC inhibition of pediatric diffuse midline glioma improves survival in murine models.

Umberto Tosi, Harikrishna Kommidi, Oluwaseyi Adeuyan, Hua Guo, Uday Bhanu Maachani, Nandi Chen, Taojunfeng Su, Guoan Zhang, David J Pisapia, Nadia Dahmane, Richard Ting, Mark M Souweidane.

Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetic monitoring. These properties would be best determined clinically with image-guided dosimetry using theranostic agents. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging and show how PETobinostat, a novel PET-imageable HDAC inhibitor, is effective against DIPG models. PET data reveal that CED has significant mouse-to-mouse variability; imaging is used to modulate CED infusions to maximize tumor saturation. The use of PET-guided CED results in survival prolongation in mouse models; imaging shows the need of CED to achieve high brain concentrations. This work demonstrates how personalized image-guided drug delivery may be useful in potentiating CED-based treatment algorithms and supports a foundation for clinical translation of PETobinostat.

DOI: https://doi.org/10.1126/sciadv.abb4105
Sci Adv. 2020 May;6(22): eaaz4125

Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients.

Vinodh N Rajapakse, Sylvia Herrada, Orit Lavi.

Although tumor invasiveness is known to drive glioblastoma (GBM) recurrence, current approaches to treatment assume a fairly simple GBM phenotype transition map. We provide new analyses to estimate the likelihood of reaching or remaining in a phenotype under dynamic, physiologically likely perturbations of stimuli ("phenotype stability"). We show that higher stability values of the motile phenotype (Go) are associated with reduced patient survival. Moreover, induced motile states are capable of driving GBM recurrence. We found that the Dormancy and Go phenotypes are equally represented in advanced GBM samples, with natural transitioning between the two. Furthermore, Go and Grow phenotype transitions are mostly driven by tumor-brain stimuli. These are difficult to regulate directly, but could be modulated by reprogramming tumor-associated cell types. Our framework provides a foundation for designing targeted perturbations of the tumor-brain environment, by assessing their impact on GBM phenotypic plasticity, and is corroborated by analyses of patient data.

DOI: https://doi.org/10.1126/sciadv.aaz4125