Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels l'expression transitoire de facteurs de reprogrammation épigénétique est susceptible d'induire le développement de tumeurs rénales analogues aux tumeurs de Wilms
Cancer is believed to arise primarily through accumulation of genetic mutations. Although induced pluripotent stem cell (iPSC) generation does not require changes in genomic sequence, iPSCs acquire unlimited growth potential, a characteristic shared with cancer cells. Here, we describe a murine system in which reprogramming factor expression in vivo can be controlled temporally with doxycycline (Dox). Notably, transient expression of reprogramming factors in vivo results in tumor development in various tissues consisting of undifferentiated dysplastic cells exhibiting global changes in DNA methylation patterns. The Dox-withdrawn tumors arising in the kidney share a number of characteristics with Wilms tumor, a common pediatric kidney cancer. We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation. These findings suggest that epigenetic regulation associated with iPSC derivation may drive development of particular types of cancer. "Transient expression of reprogramming factors leads to cancer development "Failed reprogramming-associated tumors show altered epigenetic regulation "Failed reprogramming-associated kidney tumors resemble Wilms tumor "Kidney-tumor-derived iPSCs can contribute to nonneoplastic kidney cells