Neuroblastoma patient‐derived cultures are enriched for a mesenchymal gene signature and reflect individual drug response

Hee, Esther; Wong, Ming Keong; Tan, Sheng; Choo, Zhang'e; Kuick, Chik Hong; Ling, Sharon; Yong, Ming Hui; Jain, Sudhanshi; Duan, Lian; Ng, Eileen Hui Qi; Yong, Yvonne F. L.; Ren, Mee Hiong; Sulaiman, Nurfarhanah Syed; Low, Sharon Y.Y.; Chua, Yong Wei; Syed, Muhammad Fahmy; Lim, Tony Kiat Hon; Soh, Shui Yen; Iyer, Prasad; Seng, Michaela Su-Fern; Lam, Joyce Ching Mei; Tan, Enrica Ee Kar; Chan, Mei Yoke; Tan, Ah Moy; Chen, Yong; Chen, Zhixiong; Chang, Kenneth; Loh, Amos Hong Pheng

doi:10.1111/cas.14610

Cited by 5 publications

(6 citation statements)

References 64 publications

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“…The mPDX models are cost-intensive, and not all pediatric tumors easily engraft [20]. Matrix-based organoid cultures work best for epithelial cells and are quite useful for adult carcinomas but are less applicable for embryonic (neuro)blastomas or sarcomas [30]. However, embryonic tumor cultures often spontaneously form spheroid aggregates without the need for a supportive matrix [30].…”

Section: Discussionmentioning

confidence: 99%

“…Matrix-based organoid cultures work best for epithelial cells and are quite useful for adult carcinomas but are less applicable for embryonic (neuro)blastomas or sarcomas [30]. However, embryonic tumor cultures often spontaneously form spheroid aggregates without the need for a supportive matrix [30]. Tissue-derived tumor spheres are hence arising as attractive models for ex vivo functional precision medicine studies of pediatric or embryonal tumors.…”

Section: Discussionmentioning

confidence: 99%

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Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Gatzweiler

Ridinger

Herter

et al. 2022

Cancers

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The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable tumor drivers and multidrug resistance. Novel personalized medicine approaches tailored to each tumor are urgently needed to improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling of tumor tissue identifies targets associated with clinical benefit in a subgroup of patients only and should be complemented with functional drug testing. In such an approach, patient-derived tumor cells are exposed to a library of approved oncological drugs in a physiological setting, e.g., in the form of animal avatars injected with patient tumor cells. We used molecularly fully characterized tumor samples from the INFORM study to compare drug screen results of individual patient-derived cell models in functional assays: (i) patient-derived spheroid cultures within a few days after tumor dissociation; (ii) tumor cells reisolated from the corresponding mouse PDX; (iii) corresponding long-term organoid-like cultures and (iv) drug evaluation with the corresponding zebrafish PDX (zPDX) model. Each model had its advantage and complemented the others for drug hit and drug combination selection. Our results provide evidence that in vivo zPDX drug screening is a promising add-on to current functional drug screening in precision medicine platforms.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Gatzweiler

Ridinger

Herter

et al. 2022

Cancers

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“…Concurrently, PDCs were generated from the same 13 tumors and their recapitulation of the corresponding original tumors were validated as previously described ( 15 ) ( Supplementary Data 3 ). To evaluate the ex vivo drug response phenotype, PDCs in log-phase growth were screened against an established 418-compound targeted inhibitor library and cytotoxicity normalized against DMSO negative controls (see Supplementary Data 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…PDCs were generated as previously described by explant culture under growth conditions of 37°C with 5% CO 2 ( 15 ), and passaged at 1:2 split ratio upon reaching 80-100% confluence ( 15 ). For each PDC line, optimal seeding density to achieve 72-hour log-phase growth was determined.…”

Section: Methodsmentioning

confidence: 99%

“…Commercial cell lines are often significantly changed with multiple serial passages or have been contaminated over time, and do not capture individual patient genetic or phenotypic differences in treatment response (11)(12)(13)(14). We previously developed multi-lineage patient-derived cell cultures (PDCs) of neuroblastoma from pre-and post-treatment tumors and demonstrated their recapitulation of original tumors' chromosomal alterations, immunohistochemical and gene expression profiles, and ability to predict individualized responses to standard-of-care chemotherapy (15). However, the utility of patient-derived models for prediction of targeted therapies for neuroblastoma have not been well studied.…”

Section: Introductionmentioning

confidence: 99%

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Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma

Wong

Kuick

et al. 2021

Front. Oncol.

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Neuroblastoma is the commonest extracranial pediatric malignancy. With few recurrent single nucleotide variations (SNVs), mutation-based precision oncology approaches have limited utility, but its frequent and heterogenous copy number variations (CNVs) could represent genomic dependencies that may be exploited for personalized therapy. Patient-derived cell culture (PDC) models can facilitate rapid testing of multiple agents to determine such individualized drug-responses. Thus, to study the relationship between individual genomic aberrations and therapeutic susceptibilities, we integrated comprehensive genomic profiling of neuroblastoma tumors with drug screening of corresponding PDCs against 418 targeted inhibitors. We quantified the strength of association between copy number and cytotoxicity, and validated significantly correlated gene-drug pairs in public data and using machine learning models. Somatic mutations were infrequent (3.1 per case), but copy number losses in 1p (31%) and 11q (38%), and gains in 17q (69%) were prevalent. Critically, in-vitro cytotoxicity significantly correlated only with CNVs, but not SNVs. Among 1278 significantly correlated gene-drug pairs, copy number of GNA13 and DNA damage response genes CBL, DNMT3A, and PPM1D were most significantly correlated with cytotoxicity; the drugs most commonly associated with these genes were PI3K/mTOR inhibitor PIK-75, and CDK inhibitors P276-00, SNS-032, AT7519, flavopiridol and dinaciclib. Predictive Markov random field models constructed from CNVs alone recapitulated the true z-score-weighted associations, with the strongest gene-drug functional interactions in subnetworks involving PI3K and JAK-STAT pathways. Together, our data defined individualized dose-dependent relationships between copy number gains of PI3K and STAT family genes particularly on 17q and susceptibility to PI3K and cell cycle agents in neuroblastoma. Integration of genomic profiling and drug screening of patient-derived models of neuroblastoma can quantitatively define copy number-dependent sensitivities to targeted inhibitors, which can guide personalized therapy for such mutationally quiet cancers.

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Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy

et al. 2022

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Glioblastomas are the most malignant brain tumors, whose progress was promoted by aberrate aerobic glycolysis. The immune environment was highly engaged in glioblastoma formation, while its interaction with aerobic glycolysis remained unclear. Herein, we build a 7-gene Glycolytic Score (GS) by Elastic Net in the training set and two independent validating sets. The GS predicted malignant features and poor survival with good performances. Immune functional analyses and Cibersort calculation identified depressed T cells, B cells, natural killer cells immunity, and high immunosuppressive cell infiltration in the high-GS group. Also, high expressions of the immune-escape genes were discovered. Subsequently, the single-cell analyses validated the glycolysis-related immunosuppression. The functional results manifested the high-GS neoplastic cells’ association with T cells, NK cells, and macrophage function regulation. The intercellular cross-talk showed strong associations between high-GS neoplastic cells and M2 macrophages/microglia in several immunological pathways. We finally confirmed that ENO1, the key gene of the GS, promoted M2 microglia polarization and glioblastoma cell malignant behaviors via immunofluorescence, clone formation, CCK8, and transwell rescue experiments. These results indicated the interactions between cancerous glycolysis and immunosuppression and glycolysis’ role in promoting glioblastoma progression. Conclusively, we built a robust model and discovered strong interaction between GS and immune, shedding light on prognosis management improvement and therapeutic strategies development for glioblastoma patients.

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Neuroblastoma patient‐derived cultures are enriched for a mesenchymal gene signature and reflect individual drug response

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 5 publications

References 64 publications

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

Integrated Genomic Profiling and Drug Screening of Patient-Derived Cultures Identifies Individualized Copy Number-Dependent Susceptibilities Involving PI3K Pathway and 17q Genes in Neuroblastoma

Glioblastoma glycolytic signature predicts unfavorable prognosis, immunological heterogeneity, and ENO1 promotes microglia M2 polarization and cancer cell malignancy

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