Abstract B05: Patient-derived GBM tumors versus patient-derived primary cells and GBM cell lines: lessons from microRNA profiling

Glioblastoma multiforme is a very heterogeneous tumor, highly infiltrative, angiogenic and resistant to standard therapeutic intervention. Experimental models currently used in research are mostly based on cancer cell lines, which are grown in culture for many generations and have lost many essential biological characteristics. In consequence, the xenograft tumor models derived from those cells do not maintain genomic and phenotypic characteristics present in the original tumor. It is questionable whether these artificial preclinical models can serve as reliable platforms to select the lead candidate for a novel therapeutic approach.

We utilized miRNA expression patterns to evaluate the clinical relevance of some of the currently available experimental models of GBM, searching for similarities and differences in miRNA expression levels between freshly isolated tumors, patient-derived primary cells and GBM cell lines grown in culture. The study included 22 formalin-fixed paraffin-embedded (FFPE) tumors from glioblastoma resections. Those were divided into two groups of Short Term Survivors (STS, survived up to 3 months from initial diagnosis; n=12) and Long Term Survivors (LTS, survived more than 3 years from initial diagnosis; n=10).We further tested 6 patient-derived primary cells, and 5 ATCC human GBM cell lines widely used in preclinical research. Two of the cell lines included dormant and fast-growing variants previously developed in our laboratory to resemble LTS and STS phenotypes, respectively. Samples were loaded on custom microRNA (miR) arrays, including 2172 known miRNAs (miRBase 19).

We found several miRNAs that were upregulated in the STS samples while others exhibited higher expression levels in the LTS samples.

Both GBM cell lines and patient-derived primary cells exhibited a miRNA profile which was very different from patient samples. Brain miRNAs used as brain markers, such as hsa-miR-124-3p), show relatively low expression levels in both patient-derived primary cells and commercial cell lines but are highly expressed in tumors.

We concluded that GBM experimental models must be reevaluated and pre-clinical findings derived from long-established and commonly used in vitro and in vivo models should be further validated in patient-derived models that are more suitable to evaluate the potential clinical relevance of new therapeutics.

Citation Format: Paula Ofek, Nir Dromi, Noga Yerushalmi, Sharon Kredo-Russo, Rachel Grossman, Zvi Ram, Ronit Satchi-Fainaro. Patient-derived GBM tumors versus patient-derived primary cells and GBM cell lines: lessons from microRNA profiling. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B05.