Establishment and characterization of patient-derived cancer models of malignant peripheral nerve sheath tumors

Abstract

Background Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of soft-tissue sarcoma, derived from a peripheral branch or the sheath of the sciatic nerve, brachial plexus, or sacral plexus. The clinical outcomes for MPNST patients with unresectable or metastatic tumors are dismal, and novel therapeutic strategies are required. Although patient-derived cancer cell lines are vital for basic research and preclinical studies, few MPNST cell lines are available from public cell banks. Therefore, the aim of this study was to establish cancer cell lines derived from MPNST patients. Methods We used tumor tissues from five patients with MPNSTs, including one derived from a rare bone tissue MPNST. The tumor tissues were obtained at the time of surgery and were immediately processed to establish cell lines. A patient-derived xenograft was also established when a sufficient amount of tumor tissue was available. The characterization of established cells was performed with respect to cell proliferation, spheroid formation, and invasion. The mutation status of actionable genes was monitored by NCC Oncopanel, by which the mutation of 114 genes was assessed by next-generation sequencing. The response to anti-cancer agents, including anti-cancer drugs approved for the treatment of other malignancies was investigated in the established cell lines. Results We established five cell lines (NCC-MPNST1-C1, NCC-MPNST2-C1, NCC-MPNST3-C1, NCC-MPNST4-C1, and NCC-MPNST5-C1) from the original tumors, and also established patient-derived xenografts (PDXs) from which one cell line (NCC-MPNST3-X2-C1) was produced. The established MPNST cell lines proliferated continuously and formed spheroids while exhibiting distinct invasion abilities. The cell lines had typical mutations in the actionable genes, and the mutation profiles differed among the cell lines. The responsiveness to examined anti-cancer agents differed among cell lines; while the presence of an actionable gene mutation did not correspond with the response to the anticipated anti-cancer agents. Conclusion The established cell lines exhibit various characteristics, including proliferation and invasion potential. In addition, they had different mutation profiles and response to the anti-cancer agents. These observations suggest that the established cell lines will be useful for future research on MPNSTs.

Expanding a precision medicine platform for malignant peripheral nerve sheath tumors: New patient‐derived orthotopic xenografts, cell lines and tumor entities

“…A third tumor, NF1-09, was classified as an MPNST although it has PRC2 active, which might account for the NF1-09-derived cell line clustering in the MPNST-like sarcoma group when using a methylome classifier. Moreover, these three MPNSTs presented few somatic SNVs (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), similar to other groups described in this tumor type (median of 40-60 variants) [10,11] and presented negative SOX10 and S100B staining, as expected [24,73,74,75]. A second analysis by an independent pathologist identified tumor NF1-09 as a high-grade MPNST.…”

Chromosome 8 gain is associated with high-grade transformation in MPNST

“…Global characterization of PDX lines shows significant heterogeneity Recently, PDX models have gained traction as a preclinical platform and a tool to study tumor heterogeneity. These humanized models represent a unique opportunity to study the characteristics of a large variety of tumor types, as early passage PDX lines retain a high degree of similarity to the parental tumor and allow study of tumor cell origin, biomarker identification, and treatment strategies (17)(18)(19). We generated and characterized eight NF1-MPNST PDX from eight corresponding biopsy-proven human NF1-MPNST between 2014 and 2019 at two institutions, Washington University and John Hopkins University (20).…”

Chromosome 8 gain is associated with high-grade transformation in MPNST

“…Recently, PDX models have gained traction as a preclinical platform and a tool to study tumor heterogeneity. These humanized models represent unique tools to study the characteristics of a large variety of tumor types, as early-passage PDX lines retain a high degree of similarity to the parental tumor tissues, which allows for studying the disease etiology and tumor cell origin of the human tumor ( 46 , 47 ). PDX models retain both histopathologic and genetic characteristics of the tumor donor throughout several passages.…”