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 mRNA profilling in OSKM expressing cells

将细胞重编程至多能性（cell reprogramming to pluripotency）技术应用于癌症研究后，学界已明确细胞恶性转化（transformation）与多能性为两种独立且互斥的细胞命运。若能深入阐明细胞恶性转化与重编程之间的关联，有望发现癌症治疗的全新潜在靶点与可干预弱点。本研究围绕二者的相互作用展开探索，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。本研究进一步明确，Oct4与Klf4是介导该效应的核心单一重编程因子。从分子机制来看，重编程因子下游的细胞周期抑制剂p21（cell cycle inhibitor p21）的诱导表达，是介导细胞死亡与细胞衰老的关键效应分子。本研究采用包括同种异体移植（allografts）、原位移植（orthotopic transplantation）以及KRAS驱动型肺癌小鼠模型在内的多种体内实验体系，证实OSKM的表达可抑制肿瘤生长、降低肿瘤负荷，并对表达OSKM的细胞开展了mRNA表达谱（mRNA profiling）分析。