The switch from anchorage-dependent to anchorage-independent growth is essential for epithelial metastasis. The underlying mechanism, however, is not fully understood. In this study, we identified growth factor independent-1 (GFI1), a transcription factor that drives the transition from adherent endothelial cells to suspended hematopoietic cells during hematopoiesis, as a critical regulator of anchorage independence in lung cancer cells. GFI1 elevated the numbers of circulating and lung-infiltrating tumor cells in xenograft models and predicted poor prognosis of patients with lung cancer. Mechanistically, GFI1 inhibited the expression of multiple adhesion molecules and facilitated substrate detachment. Concomitantly, GFI1 reconfigured the chromatin structure of the RASGRP2 gene and increased its expression, causing Rap1 activation and subsequent sustained ERK activation upon detachment, and this led to ERK signaling dependency in tumor cells. Our studies unveiled a mechanism by which carcinoma cells hijacked a hematopoietic factor to gain anchorage independence and suggested that the intervention of ERK signaling may suppress metastasis and improve the therapeutic outcome of patients with GFI1-positive lung cancer.

中文翻译：

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造血转录因子 GFI1 通过维持癌细胞中的 ERK 活性来促进锚定独立性

从依赖锚定生长到不依赖锚定生长的转变对于上皮转移是必不可少的。然而，潜在的机制尚不完全清楚。在这项研究中，我们确定了生长因子独立-1 (GFI1)，一种在造血过程中驱动从贴壁内皮细胞转变为悬浮造血细胞的转录因子，作为肺癌细胞锚定独立性的关键调节因子。GFI1 提高了异种移植模型中循环和肺浸润肿瘤细胞的数量，并预测肺癌患者的不良预后。从机制上讲，GFI1 抑制了多种粘附分子的表达并促进了基板分离。同时，GFI1 重新配置了RASGRP2的染色质结构基因并增加其表达，导致 Rap1 激活和随后在分离后持续的 ERK 激活，这导致肿瘤细胞中的 ERK 信号传导依赖性。我们的研究揭示了癌细胞劫持造血因子以获得锚定独立性的机制，并表明 ERK 信号传导的干预可能抑制转移并改善 GFI1 阳性肺癌患者的治疗结果。