Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors

Abstract

Background. Glioblastoma (GBM) is the deadliest primary brain cancer in adults. Emerging innovative therapies hold promise for personalized cancer treatment. Improving therapeutic options depends on research relying on relevant preclinical models. In this line we have established in the setting of the GlioTex project (GBM and Experimental Therapeutics) a GBM patient-derived cell line (GBM-PDCL) library. A multi-omic approach was used to determine the molecular landscape of PDCL and the extent to which they represent GBM tumors. Methods. Single nucleotide polymorphism array, expression arrays, exome sequencing, and RNA sequencing were used to measure and compare the molecular landscapes of 20 samples representing 10 human GBM tumors and paired GBM-PDCLs. Results. Copy number variations were similar for a median of 85% of the genome and for 59% of the major focal events. Somatic point mutations were similar in a median of 41%. Mutations in GBM driver and "druggable" genes were maintained in 67% of events. Mutations that were not conserved in the PDCL were mainly low allelic fraction and/or non-driver mutations. Based on RNA expression profiling, PDCLs cluster closely to their parental tumor with overexpression of pathways associated with cancer progression in PDCL. Conclusions. Overall, PDCLs recapitulate pivotal molecular alterations of paired-parental tumors supporting their use as a preclinical model of GBM. However, some driver aberrations are lost or gained in the passage from tumor to PDCL. Our results support using PDCL as a relevant preclinical model of GBM. Further investigations of changes between PDCLs and their parental tumor may provide insights into GBM biology.

Pleomorphism and drug resistant cancer stem cells are characteristic of aggressive primary meningioma cell lines

“…This indicated that the generated primary cell lines do represent the essence of their corresponding tumors’ tissues, as previously shown with glioblastoma multiform tumors [44]. Thus functional characteristics observed in the retrieved cell lines are likely to benefit translational research for meningiomas.…”

Temporary blood–brain barrier disruption by low intensity pulsed ultrasound increases carboplatin delivery and efficacy in preclinical models of glioblastoma

“…The molecular profiles of these six GBM PDCLs contain the principle genetic alterations reported in GBM (Online Resource 2). Cell cultures were performed as previously described [20]. GBM…”

Reflection of neuroblastoma intratumor heterogeneity in the new OHC‐NB1 disease model

“…In glioblastoma, a study of 10 matched pairs of cell lines and their source tumors reported an average overlap of 41% of somatic SNVs. 36 A comparison of ALK mutations in 2 cell lines and their originating neuroblastoma samples revealed that the oncogenic F1174L mutation was ubiquitous in all cells of both cell lines, but was detected in only 0.03% and 6.6% of cells in the originating tissues, indicating the ALK mutation provided selection pressure for the subclone in monolayer culture. 14 Another study applied whole-genome sequencing and array-based comparative genomic hybridization to compare eight neuroblastoma cell lines with the six primary tumors and two bone marrow metastases from which they were derived.…”

“…Published sequencing data of matching pairs of models and the originating tissue are rare. In glioblastoma, a study of 10 matched pairs of cell lines and their source tumors reported an average overlap of 41% of somatic SNVs . A comparison of ALK mutations in 2 cell lines and their originating neuroblastoma samples revealed that the oncogenic F1174L mutation was ubiquitous in all cells of both cell lines, but was detected in only 0.03% and 6.6% of cells in the originating tissues, indicating the ALK mutation provided selection pressure for the subclone in monolayer culture .…”