Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery

Ye, Ling F.; Reznik, Eduard; Korn, Joshua M.; Lin, Fallon; Yang, Guizhi; Malesky, Kimberly; Gao, Hui; Loo, Alice; Pagliarini, Raymond; Mikkelsen, Tom; Lo, Donald C.; deCarvalho, Ana; Stockwell, Brent R.

doi:10.18632/oncotarget.27457

Cited by 16 publications

(11 citation statements)

References 12 publications

(11 reference statements)

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“…It was reported that patient glioblastoma models vary in their sensitivities to the ferroptosis inducer RSL3 (Quartararo et al 2015). We compared the sensitivity of two GBM patient-derived models with high expression of MDM2 (Ye et al 2020), but with wild-type TP53 versus two patient-derived cell models with normal expression level of MDM2 and wild-type or mutated TP53 (Fig. 4A).…”

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MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

et al. 2020

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MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q 10 , an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

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MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

et al. 2020

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“…Hence, they demonstrate unequivocally that the artificial in vitro microenvironment changes the profile of lncRNAs related to tumor drug resistance; however, the final effect of this external influence may be contingent on changes in induced expression changes and clonal selection of cells. Using tumor primary culture as experimental models creates a chance to study tumor response including heterogeneity of particular cases (Ye et al 2020 ). Such an approach could be useful in testing potential drugs targeted to specific molecular profile of individual tumors.…”

Section: Discussionmentioning

confidence: 99%

If Artificial In Vitro Microenvironment Can Influence Tumor Drug Resistance Network via Modulation of lncRNA Expression?—Comparative Analysis of Glioblastoma-Derived Cell Culture Models and Initial Tumors In Vivo

Witusik-Perkowska¹,

Jaskólski²,

Liberski³

et al. 2020

Cell Mol Neurobiol

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The tumor resistance of glioblastoma cells in vivo is thought to be enhanced by their heterogeneity and plasticity, which are extremely difficult to curb in vitro. The external microenvironment shapes the molecular profile of tumor culture models, thus influencing potential therapy response. Our study examines the expression profile of selected lncRNAs involved in tumor resistance network in three different glioblastoma-derived models commonly utilized for testing drug response in vitro. Differential expression analysis revealed significant divergence in lncRNA profile between parental tumors and tumor-derived cell cultures in vitro, including the following particles: MALAT1, CASC2, H19, TUSC7, XIST, RP11-838N2.4, DLX6-AS1, GLIDR, MIR210HG, SOX2-OT. The examined lncRNAs influence the phenomenon of tumor resistance via their downstream target genes through a variety of processes: multi-drug resistance, epithelial–mesenchymal transition, autophagy, cell proliferation and viability, and DNA repair. A comparison of in vivo and in vitro expression identified differences in the levels of potential lncRNA targets, with the highest discrepancies detected for the MDR1, LRP1, BCRP and MRP1 genes. Co-expression analyses confirmed the following interrelations: MALAT1–TYMS, MALAT1–MRP5, H19–ZEB1, CASC2–VIM, CASC2–N-CAD; they additionally suggest the possibility of MALAT1–BCRP, MALAT1–mTOR and TUSC7–PTEN interconnections in glioblastoma. Although our results clearly demonstrate that the artificial ex vivo microenvironment changes the profile of lncRNAs related to tumor resistance, it is difficult to anticipate the final phenotypic effect, since this phenomenon is a complex one that involves a network of molecular interactions underlying a variety of cellular processes.

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“…HF2303 and HF3016 CSC lines were derived from newly diagnosed tumors from two glioblastoma patients in which MRI studies showed typical ring-enhancing lesions. These neurosphere lines were tumorigenic, and molecular profiling show that genomic abnormalities present in the parental tumors were preserved in these models [ 17 , 29 , 30 ].…”

Section: Methodsmentioning

confidence: 99%

The impact of initial tumor microenvironment on imaging phenotype

Nagaraja

deCarvalho

Brown

et al. 2021

Cancer Treatment and Research Communications

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Models of human cancer, to be useful, must replicate human disease with high fidelity. Our focus in this study is rat xenograft brain tumors as a model of human embedded cerebral tumors. A distinguishing signature of such tumors in humans, that of contrast-enhancement on imaging, is often not present when the human cells grow in rodents, despite the xenografts having nearly identical DNA signatures to the original tumor specimen. Although contrast enhancement was uniformly evident in all the human tumors from which the xenografts’ cells were derived, we show that long-term contrast enhancement in the model tumors may be determined conditionally by the tumor microenvironment at the time of cell implantation. We demonstrate this phenomenon in one of two patient-derived orthotopic xenograft (PDOX) models using cancer stem-like cell (CSC)-enriched neurospheres from human tumor resection specimens, transplanted to groups of immune-compromised rats in the presence or absence of a collagen/fibrin scaffolding matrix, Matrigel. The rats were imaged by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and their brains were examined by histopathology. Targeted proteomics of the PDOX tumor specimens grown from CSC implanted with and without Matrigel showed that while the levels of the majority of proteins and post-translational modifications were comparable between contrast-enhancing and non-enhancing tumors, phosphorylation of Fox038 showed a differential expression. The results suggest key proteins determine contrast enhancement and suggest a path toward the development of better animal models of human glioma. Future work is needed to elucidate fully the molecular determinants of contrast-enhancement.

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Patient-derived glioblastoma cultures as a tool for small-molecule drug discovery

Cited by 16 publications

References 12 publications

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling

If Artificial In Vitro Microenvironment Can Influence Tumor Drug Resistance Network via Modulation of lncRNA Expression?—Comparative Analysis of Glioblastoma-Derived Cell Culture Models and Initial Tumors In Vivo

The impact of initial tumor microenvironment on imaging phenotype

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