增强子重塑调控乳腺癌相关成纤维细胞活化的作用及分子机制研究

静息状态的成纤维细胞NFs在癌细胞持续刺激下激活成癌相关成纤维细胞CAFs，在乳腺癌发生进展中发挥重要作用，然而其激活机制尚不清楚。在多年表观基因组学研究基础上，通过原代细胞高通量测序数据，我们发现乳腺癌CAFs具有特异的活性增强子特征。以增强子为切入点，寻找到c-JUN可能为调控乳腺癌CAFs激活的关键驱动因子。成纤维细胞中过表达c-JUN可改变其染色质开放状态，促进乳腺癌细胞迁移。课题拟从细胞、动物水平探究c-JUN对乳腺癌CAFs促癌功能的影响，阐明其调控乳腺癌CAFs的激活和活性的维持的功能。ChIP-seq、ATAC-seq联合分析，明确c-JUN在乳腺癌CAFs激活过程中重塑增强子的重要作用。使用c-JUN敲除小鼠和自发乳腺癌小鼠模型探索靶向CAFs中c-JUN的潜在价值。该课题旨在揭示c-JUN调控的增强子重塑驱动了乳腺癌CAFs的激活，为靶向CAFs治疗乳腺癌提供新思路。

Normal fibroblasts (NFs) are usually quiescent and become activated cancer-associated fibroblasts (CAFs) in response to sustained stimulation of cancer cells. CAFs play a crucial role during the progression of breast cancer. However, its activation mechanism is still unclear. On the basis of many years of epigenomics research, we found that breast CAFs have specific active enhancers signature through high-throughput sequencing data of primary cells. Taking the enhancers as the entry point, we found that c-JUN may be the key driver of CAFs activation in breast cancer. Overexpression of c-JUN in fibroblasts can change the open state of chromatin and promote the migration of breast cancer cells. This study intends to explore the effect of c-JUN on breast CAFs’ cancer-promoting function at the cellular and animal levels, and to elucidate its regulation in breast cancer CAFs activation and activity maintenance. We aim to clarify the important role of c-JUN in enhancers remodeling during the activation of breast CAFs by joint analysis of ChIP-seq and ATAC-seq. To explore the potential therapeutic value of targeting c-JUN in breast CAFs, we will use c-JUN knockout mice and spontaneous breast cancer mouse models. The purpose of this project is to reveal that c-JUN-dependent enhancer remodeling drives the activation of breast CAFs and to provide a new idea for targeting CAFs in breast cancer treatment.