HDGF介导CAFs促进NSCLC肿瘤干细胞维持在化疗耐药中的功能和机制研究

肺癌的发病率和死亡率在各恶性肿瘤中均居于前列，化疗仍然是其最主要的治疗方式。目前针对非小细胞肺癌化疗耐药研究遇到了瓶颈，而肿瘤相关成纤维细胞和肿瘤干细胞可能是打破这一瓶颈的新靶点。我们前期实验结果表明NSCLC化疗耐药患者组织中大量CAFs浸润，并证实非小细胞肺癌CAFs通过HDGF促进NSCLC肿瘤细胞干性，致使化疗药物耐受。进一步实验发现HDGF/IGF1R/ERK1/2信号通路，类似于介导CAFs促进CSCs诱导化疗耐药功能的“桥梁”。因此，本课题拟从科室收集的NSCLC化疗耐受患者以及建立的PDTXs模型和CAFs原代细胞为研究对象，探讨HDGF介导CAFs在NSCLC干细胞获得和维持以及化疗耐药中的作用和分子机制；揭示HDGF、相互作用受体及其调控因子特性调控的分子网络和关键节点；为阐明CAFs在NSCLC化疗耐药中发生的分子调控机制以及预后判断、治疗分子靶标研究提供新线索。

Lung cancer is still the leading cause of cancer related death both in the world and China. More than 80% of lung cancer is non-small cell lung cancer (NSCLC), and most NSCLC patients are diagnosed at a late stage. Currently, chemotherapy and targeted therapy are two main strategies in the treatment of advanced NSCLC. Approximately one third of the patients with advanced NSCLC will initially respond to platinum-based chemotherapy, but virtually all tumors will acquired resistance. However, efforts to identify and develop novel and effective drugs to treat NSCLC have been disappointing, and improvements in survival prognosis have been very limited in recent decades. Therefore, novel drugs and therapeutic regimens are needed to overcome NSCLC. An important challenge in addressing this need is the establishment of suitable models to accurately assess the potential antitumor activity of novel therapies. NSCLC carcinoma-associated fibroblasts (CAFs) and cancer stem cells (CSCs) may be new targets to break the bottleneck. The results of our previous experiments showed that a large number of CAFs infiltrated in the tissues of NSCLC chemoresistance patients, and confirmed that NSCLC CAFs promoted the NSCLC tumor cell stemness through HDGF, resulting in resistance to chemotherapeutic drugs. Further experiments found that the HDGF/IGF1R/ERK1/ 2 signaling pathway is similar to the “bridge” that mediates CAFs to promote CSCs to induce resistance to chemotherapy. Therefore, in this study, we will focus on the patients with NSCLC chemotherapy tolerance, PDTXs model and CAFs collected from our Department, to explore the role and molecular mechanism of HDGF mediated CAFs in lung cancer stem cell acquisition and maintenance, as well as chemotherapy resistance. The aims of the study are revealing the molecular network and key nodes of HDGF, receptors and their regulatory factors and clarifying the role of CAFs in NSCLC chemotherapy resistance. This study would contribute to the understanding of the CAFs in NSCLC chemotherapy resistance at both the cellular and molecular levels and advance the development of prognostic and therapeutic strategies.