Testicular germ cell tumors (TGCTs) are the most common form of cancer in young men. They are associated with defects in embryonic male germ cell development, but the dynamic cellular processes that lead to germ cell transformation are not well understood. In this issue, Jason Heaney and colleagues compare male germ cells from three different inbred mouse lines with differing TGCT-forming propensities to explore the mechanism for the initiation of TGCTs. The authors show that the expression levels of key members of the NODAL signalling pathway that induces male germ cell fate and of Nanos2, a male germ-cell determinant, are decreased in the germ cells of TGCT-susceptible strains. In addition, diminished expression of genes downstream of Nanos2 disrupted processes that were crucial to male germ cell differentiation. In the TGCT-susceptible strain, mice homozygous for knockout of Nanos2 show increased TGCT incidence compared with wild type. The authors also reveal that the initial foci of TGCTs exhibit characteristics of ‘primed’ pluripotent cells, including the expression of NANOG and OTX2, with decreasing expression of naïve pluripotency markers DAZL, STELLA and DNMT3L. From these data, the authors propose that delayed male germ-cell specification may cause cells to enter a ‘primed’-like state, forming embryonic carcinoma foci and teratomas on a susceptible genetic background. Importantly, failed lineage restriction and pluripotent state instability have both been implicated in human TGCT susceptibility by genome-wide association studies.
