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

Autor: Mei Yoke Chan, Yvonne F. L. Yong, Derrick W. Q. Lian, Zhi Xiong Chen, Enrica E. K. Tan, Michaela S. F. Seng, Sharon Ling, Min Hwee Yong, Prasad Iyer, Yong Chen, Eileen H. Q. Ng, Yong Wei Chua, Esther Hee, Meng Kang Wong, Joyce Ching Mei Lam, Muhammad Fahmy Syed, Mee Hiong Ren, Amos Hong Pheng Loh, Sharon Y.Y. Low, Tony Kiat Hon Lim, Chik Hong Kuick, Kenneth Tou En Chang, Sudhanshi Jain, Sheng Hui Tan, Zhang'e Choo, Shui Yen Soh, Ah Moy Tan, Nurfarhanah Bte Syed Sulaiman
Rok vydání: 2020
Předmět:
0301 basic medicine
Cancer Research
patient‐derived xenograft
Tyrosine 3-Monooxygenase
Antineoplastic Agents
Biology
Mice
neuroblastoma
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Clinical Research
Cell Line
Tumor
Neuroblastoma
Gene expression
medicine
Animals
Humans
Precision Medicine
Cyclophosphamide
Homeodomain Proteins
N-Myc Proto-Oncogene Protein
cell culture
Mesenchymal stem cell
hemic and immune systems
personalized medicine
General Medicine
Gene signature
medicine.disease
Gene Expression Regulation
Neoplastic
030104 developmental biology
mesenchymal gene signature
Oncology
Cell culture
030220 oncology & carcinogenesis
Cancer research
Heterografts
N-Acetylgalactosaminyltransferases
Immunohistochemistry
Original Article
Topotecan
Transcriptome
Ex vivo
Transcription Factors
Zdroj: Cancer Science
ISSN: 1349-7006
1347-9032
Popis: Ex vivo evaluation of personalized models can facilitate individualized treatment selection for patients, and advance the discovery of novel therapeutic options. However, for embryonal malignancies, representative primary cultures have been difficult to establish. We developed patient‐derived cell cultures (PDCs) from chemo‐naïve and post–treatment neuroblastoma tumors in a consistent and efficient manner, and characterized their in vitro growth dynamics, histomorphology, gene expression, and functional chemo‐response. From 34 neuroblastoma tumors, 22 engrafted in vitro to generate 31 individual PDC lines, with higher engraftment seen with metastatic tumors. PDCs displayed characteristic immunohistochemical staining patterns of PHOX2B, TH, and GD2 synthase. Concordance of MYCN amplification, 1p and 11q deletion between PDCs and patient tumors was 83.3%, 72.7%, and 80.0% respectively. PDCs displayed a predominantly mesenchymal‐type gene expression signature and showed upregulation of pro‐angiogenic factors that were similarly enriched in culture medium and paired patient serum samples. When tested with standard‐of‐care cytotoxics at human C max‐equivalent concentrations, MYCN‐amplified and non‐MYCN‐amplified PDCs showed a differential response to cyclophosphamide and topotecan, which mirrored the corresponding patients’ responses, and correlated with gene signatures of chemosensitivity. In this translational proof‐of‐concept study, early‐phase neuroblastoma PDCs enriched for the mesenchymal cell subpopulation recapitulated the individual molecular and phenotypic profile of patient tumors, and highlighted their potential as a platform for individualized ex vivo drug‐response testing.
We developed a system to efficiently and consistently generate patient‐derived cultures (PDCs) of neuroblastoma that recapitulated individual patient’s cytogenetic and immunohistochemical features, and phenotypic responses to standard‐of‐care chemotherapy. PDCs predominantly express the gene signature of the recently described neuroblastoma mesenchymal super‐enhancer state. This proof‐of concept provides translational evidence supporting the proposed role of the mesenchymal cell subpopulation in determining clinical treatment response and offers a novel platform for developing personalized ex vivo therapeutic decision‐making strategies for neuroblastoma.
Databáze: OpenAIRE
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