Fosl1 is a transcriptional effector of BRAFV600E-driven intestinal tumorigenesis

作者：Zakia Alam, Rebecca Nightingale, Analia Lesmana, Cheng Liu, Laura J Jenkins, M. Richardson, Lawrence Croft, Ian Y Luk, Camilla M. Reehorst, F. Chionh, Natalia Vukelic, Faiza Basheer, E. Tulchinsky, J. Badshah, T. Dumenil, L. Bakiri, Erwin F Wagner, Niall C. Tebbutt, Vicki Whitehall, J. Mariadason, A. Dhillon · 发表于：iScience · 年份：2025 · DOI：10.1016/j.isci.2025.113875 · 被引用次数：2 · 研究领域：Medicine

Summary The serrated neoplasia pathway is an alternate route to colorectal cancer (CRC) development where BRAFV600E is the most common initiating genetic alteration. BRAFV600E-driven tumorigenesis requires gene expression changes mediated by activation of the ERK MAPK signaling pathway. However, the key effectors of this process are elusive. Here, we identify the ERK-regulated transcription factor Fosl1, one such effector. We show that Fosl1 is dispensable for the initiation of BRAFV600E-driven serrated neoplasia in mice but promotes progression of the disease by regulating the expression of genes involved in inflammation, immunity, cell cycle control, fetal-like programming, and gastric metaplasia. Notably, transgenic Fosl1 expression alone was sufficient to induce tumors with a BRAFV600E-like serrated morphology and transcriptional profile. These findings reveal a mechanism through which oncogenic BRAF-driven ERK signaling reprograms transcription to drive serrated neoplasia.