scholarly journals Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma

2020 ◽  
Vol 12 (562) ◽  
pp. eaba4434
Author(s):  
Karin Hansson ◽  
Katarzyna Radke ◽  
Kristina Aaltonen ◽  
Jani Saarela ◽  
Adriana Mañas ◽  
...  
Keyword(s):  
High Risk ◽  
Human Cancer ◽  
Neuroblastoma Cell ◽  
Human Tumor ◽  
Loss Of Function ◽  
Human Cancer Cell Lines ◽  
Dismal Prognosis ◽  
Tumor Types ◽  
Genome Scale

Neuroblastoma is a childhood malignancy with often dismal prognosis; relapse is common despite intense treatment. Here, we used human tumor organoids representing multiple MYCN-amplified high-risk neuroblastomas to perform a high-throughput drug screen with approved or emerging oncology drugs. Tumor-selective effects were calculated using drug sensitivity scores. Several drugs with previously unreported anti-neuroblastoma effects were identified by stringent selection criteria. ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability. High expression of the KSP-encoding gene KIF11 was associated with poor outcome in neuroblastoma. Genome-scale loss-of-function screens in hundreds of human cancer cell lines across 22 tumor types revealed that KIF11 is particularly important for neuroblastoma cell viability. KSP inhibition in neuroblastoma patient-derived xenograft (PDX) cells resulted in the formation of abnormal monoastral spindles, mitotic arrest, up-regulation of mitosis-associated genes, and apoptosis. In vivo, KSP inhibition caused regression of MYCN-amplified neuroblastoma PDX tumors. Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma.

Phosphate dysregulation via the XPR1:KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer

2020 ◽  
Author(s):  
Daniel P Bondeson ◽  
Brenton R Paolella ◽  
Adhana Asfaw ◽  
Michael Rothberg ◽  
Thomas Skipper ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Uterine Cancer ◽  
Cancer Cell Lines ◽  
Loss Of Function ◽  
Human Cancer Cell Lines

Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/ Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

scholarly journals YKL-40 protein expression in human tumor samples and human tumor cell line xenografts: implications for its use in tumor models

2021 ◽  
Author(s):  
Lukas Clemens Böckelmann ◽  
Theresa Felix ◽  
Simona Calabrò ◽  
Udo Schumacher
Keyword(s):  
Protein Expression ◽  
Tumor Cell ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Human Tumor ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Tumor Entities

Abstract Background YKL-40, also known as non-enzymatic chitinase-3 like-protein-1 (CHI3L1), is a glycoprotein expressed and secreted mainly by inflammatory cells and tumor cells. Accordingly, several studies demonstrated elevated YKL-40 serum levels in cancer patients and found YKL-40 to be correlated with a poor prognosis and disease severity in some tumor entities. YKL-40 was suggested to be involved in angiogenesis and extracellular matrix remodeling. As yet, however, its precise biological function remains elusive. Methods As YKL-40 protein expression has only been investigated in few malignancies, we employed immunohistochemical detection in a large multi-tumor tissue microarray consisting of 2,310 samples from 72 different tumor entities. In addition, YKL-40 protein expression was determined in primary mouse xenograft tumors derived from human cancer cell lines. Results YKL-40 could be detected in almost all cancer entities and was differently expressed depending on tumor stage and subtype (e.g., thyroid cancer, colorectal cancer, gastric cancer and ovarian cancer). While YKL-40 was absent in in vitro grown human cancer cell lines, YKL-40 expression was upregulated in xenograft tumor tissues in vivo. Conclusions These data provide new insights into YKL-40 expression at the protein level in various tumor entities and its regulation in tumor models. Our data suggest that upregulation of YKL-40 expression is a common feature in vivo and is finely regulated by tumor cell-microenvironment interactions.

scholarly journals Hmox1 Upregulation Is a Mutual Marker in Human Tumor Cells Exposed to Physical Plasma-Derived Oxidants

Antioxidants ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 151 ◽  
Author(s):  
Sander Bekeschus ◽  
Eric Freund ◽  
Kristian Wende ◽  
Rajesh Gandhirajan ◽  
Anke Schmidt
Keyword(s):  
Cell Lines ◽  
Human Cancer ◽  
Human Tumor ◽  
Heme Oxygenase 1 ◽  
Human Cancer Cell Lines ◽  
Baseline Activity ◽  
New Treatment ◽  
Physical Plasma

Increasing numbers of cancer deaths worldwide demand for new treatment avenues. Cold physical plasma is a partially ionized gas expelling a variety of reactive oxygen and nitrogen species, which can be harnesses therapeutically. Plasmas and plasma-treated liquids have antitumor properties in vitro and in vivo. Yet, global response signatures to plasma treatment have not yet been identified. To this end, we screened eight human cancer cell lines to investigate effects of low-dose, tumor-static plasma-treated medium (PTM) on cellular activity, immune-modulatory properties, and transcriptional levels of 22 redox-related genes. With PTM, a moderate reduction of metabolic activity and modest modulation of chemokine/cytokine pattern and markers of immunogenic cell death was observed. Strikingly, the Nuclear factor (erythroid-derived 2)-like 2 (nrf2) target heme oxygenase 1 (hmox1) was upregulated in all cell lines 4 h post PTM-treatment. nrf2 was not changed, but its baseline expression inversely and significantly correlated with hmox1 expression after exposure to PTM. Besides awarding hmox1 a central role with plasma-derived oxidants, we present a transcriptional redox map of 22 targets and chemokine/cytokine secretion map of 13 targets across eight different human tumor cell lines of four tumor entities at baseline activity that are useful for future studies in this field.

High-risk HPV-positive human cancer cell lines show different sensitivity to cisplatin-induced apoptosis correlated with the p21Waf1/Cip1 level

1996 ◽  
Vol 108 (1) ◽  
pp. 15-23 ◽  
Author(s):  
Kohsei Funaoka ◽  
Masanobu Shindoh ◽  
Toshiharu Yamashita ◽  
Kei Fujinaga ◽  
Akira Amemiya ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Induced Apoptosis ◽  
High Risk Hpv

scholarly journals AKT1-CREB stimulation of PDGFRα expression is pivotal for PTEN deficient tumor development

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Xiaofeng Wan ◽  
Meng Zhou ◽  
Fuqiang Huang ◽  
Na Zhao ◽  
Xu Chen ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Human Cancer ◽  
Critical Role ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Conditional Knockout ◽  
Loss Of Function ◽  
Akt Inhibitor ◽  
Human Cancer Cell Lines ◽  
Direct Binding

AbstractAs evidenced by the behavior of loss-of-function mutants of PTEN in the context of a gain-of-function mutation of AKT1, the PTEN-AKT1 signaling pathway plays a critical role in human cancers. In this study, we demonstrated that a deficiency in PTEN or activation of AKT1 potentiated the expression of platelet-derived growth factor receptor α (PDGFRα) based on studies on Pten−/− mouse embryonic fibroblasts, human cancer cell lines, the hepatic tissues of Pten conditional knockout mice, and human cancer tissues. Loss of PTEN enhanced PDGFRα expression via activation of the AKT1-CREB signaling cascade. CREB transactivated PDGFRα expression by direct binding of the promoter of the PDGFRα gene. Depletion of PDGFRα attenuated the tumorigenicity of Pten-null cells in nude mice. Moreover, the PI3K-AKT signaling pathway has been shown to positively correlate with PDGFRα expression in multiple cancers. Augmented PDGFRα was associated with poor survival of cancer patients. Lastly, combination treatment with the AKT inhibitor MK-2206 and the PDGFR inhibitor CP-673451 displayed synergistic anti-tumor effects. Therefore, activation of the AKT1-CREB-PDGFRα signaling pathway contributes to the tumor growth induced by PTEN deficiency and should be targeted for cancer treatment.

scholarly journals Impact of extracellular matrix properties on neuroblastoma genomic heterogeneity

2020 ◽  
Author(s):  
Amparo López-Carrasco ◽  
Susana Martín-Vañó ◽  
Rebeca Burgos-Panadero ◽  
Ezequiel Monferrer ◽  
Ana P Berbegall ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
High Risk ◽  
Cell Lines ◽  
Neuroblastoma Cell ◽  
Chromosome 9 ◽  
Future Research ◽  
Knock Out ◽  
Specific Distribution

Abstract Background Increased tissue stiffness is a common feature of malignant solid tumors, often associated with metastasis and poor patient outcomes. Vitronectin, as an extracellular matrix anchorage glycoprotein related to a stiff matrix, is present in a particularly increased quantity and specific distribution in high-risk neuroblastoma. Furthermore, as cells can sense and transform the proprieties of the extracellular matrix into chemical signals through mechanotransduction, genotypic changes related to stiffness are possible. Methods We have applied high density SNPa and NGS techniques to in vivo and in vitro models (orthotropic xenograft vitronectin knock-out mice and 3D bioprinted hydrogels with different stiffness) using two representative neuroblastoma cell lines (the MYCN amplified SK-N-BE(2) and the ALK mutated SH-SY5Y), to discern how tumor genomics patterns and clonal heterogeneity of both cell lines are affected. Results We describe a remarkable subclonal selection of some genomic aberrations in SK-N-BE(2) cells grown in knock-out vitronectin xenograft mice that also emerged when cultured for long times in stiff hydrogels. Specially, we detected an enlarged subclonal cell population with chromosome 9 aberrations in both models. Similar abnormalities were found in human high-risk neuroblastoma with MYCN amplification. Genomics of the SH-SY5Y cell line remained stable when cultured in both models. Conclusions Focus on heterogeneous intratumor segmental chromosome aberrations and mutations, as a mirror image of tumor microenvironment, is a vital area of future research.

scholarly journals PPM1D is a neuroblastoma oncogene and therapeutic target in childhood neural tumors

2020 ◽  
Author(s):  
Jelena Milosevic ◽  
Susanne Fransson ◽  
Miklos Gulyas ◽  
Gabriel Gallo-Oller ◽  
Thale K Olsen ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Genetic Manipulation ◽  
Clonal Evolution ◽  
Neuroblastoma Cell ◽  
Tumor Formation ◽  
T Cell Lymphomas ◽  
Wip1 Phosphatase ◽  
Bona Fide ◽  
Genome Scale

SUMMARYMajority of cancers harbor alterations of the tumor suppressor TP53. However, childhood cancers, including unfavorable neuroblastoma, often lack TP53 mutations despite frequent loss of p53 function, suggesting alternative p53 inactivating mechanisms.Here we show that p53-regulating PPM1D at chromosome 17q22.3 is linked to aggressive tumors and poor prognosis in neuroblastoma. We identified that WIP1-phosphatase encoded by PPM1D, is activated by frequent segmental 17q-gain further accumulated during clonal evolution, gene-amplifications, gene-fusions or gain-of-function somatic and germline mutations. Pharmacological and genetic manipulation established WIP1 as a druggable target in neuroblastoma. Genome-scale CRISPR-Cas9 screening demonstrated PPM1D genetic dependency in TP53 wild-type neuroblastoma cell lines, and shRNA PPM1D knockdown significantly delayed in vivo tumor formation. Establishing a transgenic mouse model overexpressing PPM1D showed that these mice develop cancers phenotypically and genetically similar to tumors arising in mice with dysfunctional p53 when subjected to low-dose irradiation. Tumors include T-cell lymphomas harboring Notch1-mutations, Pten-deletions and p53-accumulation, adenocarcinomas and PHOX2B-expressing neuroblastomas establishing PPM1D as a bona fide oncogene in wtTP53 cancer and childhood neuroblastoma. Pharmacological inhibition of WIP1 suppressed the growth of neural tumors in nude mice proposing WIP1 as a therapeutic target in neural childhood tumors.

scholarly journals Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Pouyan Ghaffari ◽  
Adil Mardinoglu ◽  
Anna Asplund ◽  
Saeed Shoaie ◽  
Caroline Kampf ◽  
...  
Keyword(s):  
Growth Factors ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Metabolic Modeling ◽  
Cancer Cell Lines ◽  
Human Cancer Cell ◽  
Human Cancer Cell Lines ◽  
Genome Scale

scholarly journals The effect of CELLFOODTM on radiotherapy or combined chemoradiotherapy: preclinical evidence

2019 ◽  
Vol 11 ◽  
pp. 175883591987834
Author(s):  
Barbara Nuvoli ◽  
Bruno Amadio ◽  
Giancarlo Cortese ◽  
Serena Benedetti ◽  
Barbara Antoniani ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumour Growth ◽  
Human Cancer ◽  
Combined Treatment ◽  
Treatment Strategies ◽  
Phosphoglycerate Kinase ◽  
Immunohistochemical Analysis ◽  
Chemotherapy Treatment ◽  
Human Cancer Cell Lines

Background: Based on previous observations that the nutraceutical CELLFOOD™ (CF), the ‘physiological modulator’ that aimed to make oxygen available ‘on demand’, inhibits the growth of cancer cells, this study was designed to investigate the role of CF in the regulation of hypoxia-inducible factor 1 alpha (HIF1α) and its correlated proteins, phosphoglycerate kinase 1 and vascular endothelial growth factor. Our idea was that CF, acting on HIF1α, in combination with current anticancer therapies could improve their effectiveness. Methods: To evaluate the effect of CF in association with radiotherapy and chemotherapy, different human cancer cell lines and mice with mesothelioma were analysed by tumour growth, clonogenic assay, western blot and immunohistochemical analysis. Results: CF in combination with radiation with or without cisplatin increases the death rate of cancer cells. In vivo, 70% of mice treated with CF before the mesothelioma graft did not show any tumour growth, indicating a possible preventive effect of CF. Moreover, in mouse mesothelioma xenografts, CF improves the effect of radiotherapy also in combination with chemotherapy treatment. Immunohistochemical analysis of tumour explants showed that HIF1α expression was reduced by the combination of CF and radiotherapy treatment and even more by the combination of CF and radiotherapy and chemotherapy treatment. Mechanistically, CF increases the fraction of oxygenated cells, making the radiotherapy more effective with a greater production of reactive oxygen species (ROS) that in turn, reduce the HIF1α expression. This effect is amplified by further increase in ROS from chemotherapy. Conclusions: Collectively, results from preclinical trials suggest that CF could be a useful intervention to improve the efficacy of radiotherapy or combined treatment strategies and could be a promising treatment modality to counteract cancer.

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