Exploiting endogenous retroviruses in squamous cancers
Introduction
Known as molecular fossils or genetic parasites that invaded our genome through ancestral lineages, mammalian transposons (mainly retrotransposons) are interspersed genomic repeats that constitute more than 40% of the genome. Most retrotransposons are either degenerated or domesticated as host regulome to orchestrate lineage gene expressions, while an extraordinary group morphed into host proteins or donated coding functions during a critical stage of mammalian development. A few rare evolutionarily young species remain virally active and are responsible for germline mutations and modulate immune functions. Retrotransposon activities have been widely observed in adult pathologies such as autoimmunity, neurodegeneration, aging, and cancer, although the extent to which retrotransposons engage viral life cycle is unclear. Their molecular trigger in adult physiology and pathology remains poorly defined.
Methods
We sought to tackle this question in the murine skin, which is maintained by long-term self-renewal and multi-potent adult stem cells. As our largest organ, skin serves as a physical barrier to preserve body fluid, guard against irradiation and pathogens and conduct sensations. Skin is a uniquely suitable system to study retrotransposon biology, given its well-characterized and readily accessible adult stem cell populations, and definitive cell of origin in squamous malignancy. I have a longstanding interest in epithelial stem cell and cancer biology. We have developed genetic and functional genomic tools in the skin that have provided valuable insights into stem cell lineage plasticity in squamous cell carcinomas. Built on these approaches, our current study exploits our unique ability to read and perturb retrotransposons in the skin epithelium for discovering cancer vulnerabilities.
Results
We saw adult hair follicle stem cells were specifically marked by the histone methyltransferase SETDB1. Its conditional ablation in the skin led to hair loss and stem cell exhaustion, accompanied by the loss of the repressive histone mark H3K9me3 (catalyzed by SETDB1) and reactivation of the endogenous retroviruses (ERVs, a type of retrotransposon). Interestingly, we observed a robust and selective surge of ERVs originated from the viral coding regions. In contrast to the well-characterized regulome function of retrotransposons, strikingly, we found these viral coding ERVs produced abundant retroviral peptides, gave rise to viral-like particles, and elicited cellular and humoral immunity in vivo. The accompanied skin pathology can be ameliorated by pharmacological or genetic inhibition of retroviral activity, suggesting functional retroviral signaling in causing the skin pathology.
Conclusion
An evolution conundrum, the viral-coding ERVs serve as a major coding reservoir of the mammalian genome, whose resident virions pose an eminent threat to host tissue fitness, a leverage to expose cancer vulnerability. By addressing molecular and cellular pathogenesis of viral-coding ERVs in the skin, our findings provided important insights into adult retrotransposon biology and therapeutic opportunities in cancer treatment.