Somatic cancers: Hijacking germ cell immortality tools

Germ cells are – arguably – the most fascinating and important cells in our bodies, as they pass their genomes from one generation to another thus establishing an immortal germline. To ensure this mission, germ cells express highly specific sets of genes fine-tuned by epigeneticmechanisms that promote cell growthand survival, together with the ability to manipulate their own chromatin in the unique process of meiosis leading to formation of haploid gametes. By contrast, somatic cells are highly morphologically differentiated and functionally specified. Except for the developmental period, somatic cells have numerous regulatory systems in place ensuring orderly cell renewal and maturation to a specialised cell type, and usually undergo a limited number of divisions before turning senescent. A failure in one or more of these systems usually leads to uncontrolled cell proliferation, transformation, and ultimately cancer. Cancer cells drift apart from their destiny and transform into ‘younger’, ‘selfish’ and unstable cells, with high phenotypic plasticity. In that they resemble in many ways the germ cells before their turn into gametes. This similarity is the topic of the ‘Hypothesis’ article in this issue of BioEssays, written by Bruggeman and colleagues.[1] The authors propose that malignancy is promoted primarily by the activation of a ‘germline programme’. This concept is not entirely new, as others have previously noticed germ cell features in somatic tumours. I would like to highlight a couple of conceptual milestones, which undoubtedly contributed to the idea of the ‘germline activation’. A key milestone was the discovery of the so-called cancer-testis (C/T) antigens expressed normally only in germ cells and ectopically in numerous somatic malignancies.[2] However, the key realisation was that the abnormal activation of these genes in somatic cancers was not only an immunological phenomenon and a consequence of global epigenetic dysregulation, but also a cause of further large-scale alterations of the epigenome, which themselves had direct oncogenic consequences for the affected cells.[3] It was subsequently confirmed that the ectopic expression of theC/T genes in somatic cells causes genomic instability, because of the interference with homologous recombination – the most important physiological DNA break-related function indispensable for the genomic renewal in germ cells.[4] Bruggeman et al. developed this idea into a more comprehensive induction of germline programme in somatic cancer cells that encompasses not only the activation of meiotic genes and epigenetic instability but also metabolic plasticity and propensity to invasion, which can be linked to embryonic migration of primordial germ cells.[1] The idea of the preferential germline-like transformation of somatic cancer cells contrasts with another currently discussed hypothesis stipulating that hypomethylated and ‘unstable’ chromatin promotes stochastic gene expression changes leading to its ‘aggressiveness ’, increasing malignancy and spread of the tumour.[5] Bruggeman et al. are experts in germ cell biology, hence, they argue eloquently for a non-random activationofmeiotic genes in cancer, andprovide a great deal of supporting evidence from their own bioinformatic analysis of hallmark germline features in several somatic cancers.[1] The jury is still out which of the twoconcepts ismost plausible, anddetailedmechanistic studies of cancer cells in humans and other species are needed to establish which events – genomic rearrangements linked to induction of meiosis – or rather epigenetic adaptation – are the first events triggeringmalignant transformation of somatic cells. Finally, I would like to highlight one unexplained mystery: why does malignant transformation of germ cells often trigger molecular events that are the exact opposite of the somatic cancer transformation? It is quite common that when invasive germ cell tumours develop – the immature germ cell-like features of the precursor cell profoundly change; with increasing genome methylation, downregulation of pluripotency genes and widespread differentiation towards somatic-like tissues, which is a hallmark of teratomas. This paradox is a proof that nothing in cell biology is carved in stone. . . Stay tuned. This article comments on the hypothesis paper by Bruggeman et al., https://doi.org/10.1002/bies.202200112