Studying glioblastoma cell culture vs tumor in the patient — showed striking differences

Glioblastoma is the most deadly form of brain cancer in adults. This cancer is responsible for more than 12,000 brain-tumor diagnoses in the U.S each year. Extensive characterization of its molecular basis, largely made possible recently, through massive genomic studies –– has provided a compre­hensive understanding of some of the major cancer-causing genes and aberrant pathways that underlie glioblastoma development, relapse and resist­ance. However, putative therapies that target these genes and pathways have so far shown little success in clinical glioblastoma trials. In the attached article and editorial, authors report their results from an elegant systematic screen aimed to identify therapeutic targets for glioblastoma that regulate the epi­genome (i.e. multiple heritable chemical modifications that control gene activity with­out altering the underlying DNA sequence).

As often discussed in these GEITP emails, epigenetic modifications include DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling. The presence of methyl groups on cytosine residues, and those on histone proteins (including methylation, acetylation and phosphorylation) –– around which DNA is packaged –– comprises such epigenetic effects. Collectively, these modifications can dictate whether genes are expressed or silent, typically in a cell-type-specific manner. Enzymes called epigenetic modifiers are responsible for establishing, maintaining, reading, and removing these modifications in a highly orchestrated, multifaceted manner.

Authors [attached] investigated the cellular requirements for epigenetic modifi­ers in glioblastoma, using cancerous cells derived from patients with glio­blastoma, which were either grown in culture (which authors herein incorrectly use the term “in vitro”) or transplanted into the brains of mice (which authors herein correctly term “in vivo”). Surprisingly (and the main reason for sharing this as a GEITP email), the researchers found the candidate gene classes identified differed strikingly between experiments in culture vs in the inact animal –– with only three genes identified under both conditions. This study therefore underscores the importance of EXPERIMENTS IN THE INTACT ANIMAL, as compared with experimental results in cells in culture (in which so many artifacts can arise).

Nature July 2o17; 547: 355–359 (full article) & 191–192 (News’N’Views)

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