Failed reprogramming of transformed cells due to induction of apoptosis and senescence impairs tumor progression in lung cancer

Cell reprogramming to pluripotency applied to the study of cancer has identified transformation and pluripotency as two independent and incompatible cell fates. A detailed knowledge of the relationship between transformation and reprogramming could lead to the identification of new vulnerabilities and therapeutic targets in cancer. Here, we explore this interplay and find that OSKM expression limits tumor cell growth by inducing apoptosis and senescence. We identify Oct4 and Klf4 as the main individual reprogramming factors responsible for this effect. Mechanistically, the induction of cell cycle inhibitor p21 downstream of the reprogramming factors acts as mediator of cell death and senescence. Using a variety of in vivo systems, including allografts, orthotopic transplantation and KRAS-driven lung cancer mouse models, we demonstrate that OSKM expression impairs tumor growth and reduces tumor burden Overall design: mRNA profilling in OSKM expressing cells

将细胞重编程至多能性状态（cell reprogramming to pluripotency）应用于癌症研究后，学界已证实细胞转化（transformation）与多能性（pluripotency）为两种独立且互斥的细胞命运。深入解析细胞转化与重编程之间的关联，有望发现癌症中新的易感靶点与治疗靶标。本研究探索了二者的相互作用，发现OSKM的表达可通过诱导细胞凋亡（apoptosis）与细胞衰老（senescence）抑制肿瘤细胞增殖。我们明确Oct4与Klf4是介导该效应的核心单一重编程因子。机制层面，重编程因子下游的细胞周期抑制因子p21的诱导表达，可作为细胞死亡与细胞衰老的介导因子。我们借助多种体内实验体系，包括同种异体移植（allografts）、原位移植（orthotopic transplantation）以及KRAS驱动型肺癌小鼠模型，证实OSKM的表达可抑制肿瘤生长并降低肿瘤负荷。整体实验设计：对表达OSKM的细胞开展mRNA表达谱分析（mRNA profiling）。