肿瘤微环境通过EGR1/IL-6及外泌体参与胎盘部位滋养细胞肿瘤化疗耐药的分子机制研究

胎盘部位滋养细胞肿瘤（placental site trophoblastic tumor, PSTT）是种植部位中间型滋养细胞异常增生所导致罕见的滋养细胞疾病，其主要治疗方式为全子宫切除及辅助化疗。手术治疗使年轻PSTT患者丧失生育功能，由于大多数PSTT患者对化疗耐药，部分患者手术后仍会出现转移，甚至引起死亡。然而，PSTT化疗耐药的分子机制并不清楚。本项目前期由PSTT病灶分离肿瘤相关成纤维细胞（cancer-associated fibroblasts，CAFs)，发现其通过EGR1/IL-6促进滋养细胞对放线菌素D（ACD）耐药，同时通过分泌外泌体促进滋养细胞对甲氨蝶呤（MTX）耐药。在此基础上，本项目拟深入阐明PSTT对ACD及MTX耐药的分子机制，以期发现新的治疗靶点，同时探索与PSTT药物敏感性及预后相关的分子标记，为PSTT个体化治疗提供科学依据。

Placental site trophoblastic tumor (PSTT) is a rare gestational trophoblastic neoplasia which originates from placental site intermediate trophoblasts. The main treatment for PSTT patients is hysterectomy and adjuvant chemotherapy. Young PSTT patients were deprived of the fertility after the surgical dissection. Due to the chemoresistance of most PSTT patients, metastases still occur in partial PSTT patients and cause death. However, the underlying molecular mechanisms remain elusive. Our present study isolated the cancer-associated fibroblasts (CAFs) from PSTT lesion. We found that CAFs induced the chemoresistance to actinomycin D (ACD) of the trophoblast cells through EGR1/IL-6, and caused the chemoresistance to methotrexate (MTX) via the secretion of exosomes. On the basis of previous study, this project aim to elucidate the mechanisms by which PSTT is chemoresistant to ACD and MTX in order to find the new treatment targets and explored the biomarker correlated with the chemosensitivity and prognosis of PSTT patients, and provide the scientific evidence for the individualized treatment strategy.