Context-Dependent Impact of RAS Oncogene Expression on Cellular Reprogramming to Pluripotency

Abstract

Summary: Induction of pluripotency in somatic cells with defined genetic factors has been successfully used to investigate the mechanisms of disease initiation and progression. Cellular reprogramming and oncogenic transformation share common features; both involve undergoing a dramatic change in cell identity, and immortalization is a key step for cancer progression that enhances reprogramming. However, there are very few examples of complete successful reprogramming of tumor cells. Here we address the effect of expressing an active oncogene, RAS, on the process of reprogramming and found that, while combined expression with reprogramming factors enhanced dedifferentiation, expression within the context of neoplastic transformation impaired reprogramming. RAS induces expression changes that promote loss of cell identity and acquisition of stemness in a paracrine manner and these changes result in reprogramming when combined with reprogramming factors. When cells carry cooperating oncogenic defects, RAS drives cells into an incompatible cellular fate of malignancy. : Cellular reprogramming and oncogenic transformation share common features. Collado and colleagues show that oncogenic Ras enhances reprogramming to pluripotency in normal somatic cells in a paracrine manner. In contrast, oncogenically transformed cells are resistant to reprogramming. Oncogenic transformation raises reprogramming barriers that can be reverted by turning off the expression of the driving oncogene. Transformation and reprogramming are incompatible cell fates. Key words: Ras, oncogenes, cell reprogramming, iPSC, cell plasticity