Laboratorio de Células Madre en Cáncer y Envejecimiento, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), E15706 Santiago de Compostela, Spain.
Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), E28029 Madrid, Spain.
Stem Cell Reports. 2019 May 14;12(5):1099-1112. doi: 10.1016/j.stemcr.2019.04.006. Epub 2019 May 2.
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.
用定义明确的遗传因素诱导体细胞核重编程为多能性已成功用于研究疾病起始和进展的机制。细胞重编程和致癌转化具有共同的特征；两者都涉及细胞身份的剧烈变化，而永生化是促进重编程的癌症进展的关键步骤。然而，成功重编程肿瘤细胞的例子非常少。在这里，我们研究了表达活性致癌基因 RAS 对重编程过程的影响，发现虽然与重编程因子的联合表达增强了去分化，但在肿瘤转化的背景下表达会损害重编程。RAS 通过旁分泌方式诱导促进细胞身份丧失和获得干性的表达变化，当与重编程因子结合时，这些变化导致重编程。当细胞携带协同致癌缺陷时，RAS 将细胞推向恶性的不兼容细胞命运。
