Editors' ChoiceCancer

Human Cells: Finally Open for Cancer Business

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Science Translational Medicine  03 Sep 2014:
Vol. 6, Issue 252, pp. 252ec150
DOI: 10.1126/scitranslmed.3010262

Human cancer biology is incredibly complex. Right now, the only way to discover previously unidentified oncogenic drivers (genes with strong tumorigenic potential) in human cells is by treating them with chemical carcinogens or ionizing radiation. These approaches are not optimal because they introduce many genetic changes at once. Insertional mutagenesis with transposons is an elegant way to systematically investigate previously unknown drivers by introducing genetic material that disrupts or enhances the expression of endogenous genes and thus reveals previously unidentified tumor suppressors or oncogenes, respectively. This method works very well in zebrafish and mice, but its relevance to human cancers was previously unclear. Now, Molyneux and colleagues describe an innovative methodology that allows for high-throughput, transposon-based oncogenic screens in normal human cells.

Transposons are DNA segments that can move within the genome. Transposases are a family of enzymes that cut genomic DNA to create insertion sites that are specific for transposons. Plasmids containing a transposon and transposase can be transfected into target cells. Unfortunately, human cells are resistant to transfection. The most efficient way to deliver foreign genetic material to human cells is via transduction with engineered viruses. The authors thus decided to combine these two approaches by designing “Lentihop,” a transposon-expressing lentivirus.

To mimic the development of bone tumors (sarcoma) in vitro, the authors used normal human bone cells. They increased these cells’ oncogenic potential and their ability to deal with transposons by sequentially transducing the cells with retroviruses containing three common sarcoma oncogenes and a transposase. When these cells were injected into mice, they did not generate a mass unless they were transduced once more, with Lentihop. Amazingly, the pathology of the resulting tumors was similar to that of patient-derived sarcomas. Detailed genomic studies revealed that the transposons “landed” near many known oncogenic drivers. This method also led to the identification of a new tumor suppressor gene that encodes a RNA-binding protein (vigilin).

This proof-of-concept article highlights a promising methodology that should open the floodgates for human cell-based cancer studies, although it remains unclear whether this approach will be as efficient in cell types other than those used in this study. This is an important step because it should now be possible to study how clinically relevant oncogenic drivers behave together within human-specific cellular and genomic contexts.

S. D. Molyneux et al., Human somatic cell mutagenesis creates genetically tractable sarcomas. Nat. Genet., published online 17 August 2014 (10.1038/ng.3065).[Full Text]

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