PAX5基因通过诱导细胞转分化促进小细胞肺癌耐药发生的分子机制研究

小细胞肺癌（SCLC）恶性程度极高，易发生化疗耐药。耐药一直是SCLC临床治疗中面临的主要难题。既往研究表明SCLC高负荷的基因组突变导致其组织内细胞异质性较高，这一特性与其易发生耐药密切相关。申请人前期研究发现PAX5基因在SCLC中存在拷贝数扩增突变，且其表达水平在人体SCLC组织中显著上调并且能够促进SCLC细胞对化疗药物产生耐药。进一步研究发现PAX5能够上调YAP1表达水平并诱导ASCL1+型SCLC细胞转分化为YAP1+细胞。细胞转分化是肿瘤细胞发生耐药的机制之一。因此，我们提出PAX5上调可能通过调控YAP1介导的细胞转分化促进SCLC耐药发生的科学假说。本研究拟进一步阐明：1）PAX5是否通过上调YAP1诱导SCLC细胞转分化？2）PAX5是否通过诱导SCLC细胞转分化促进其耐药性？本研究预期将揭示调控SCLC耐药发生的关键分子机制，为其临床治疗提供潜在靶点。

Small cell lung cancer (SCLC) is extremely aggressive lung cancer, characterized by the fast emergence of chemoresistance after the initial good response to chemotherapy. Chemoresistance has been a major problem in the clinical treatment of SCLC. The genomic mutation burden of SCLC is extremely high, leading to increased intra-tumoral heterogeneity, which has been demonstrated to be critical for chemoresistance. In the previous research, we first found that the PAX5 gene has copy number amplification in SCLC, and the expression of the PAX5 gene in human SCLC primary tumors was significantly upregulated. Furthermore，PAX5 was observed to promote the chemoresistance of SCLC cells. Moreover, we found that PAX5 could upregulate the expression of YAP1 gene in ASCL1+ SCLC cells and induce ASCL1+ cells to transdifferentiate to YAP1+ cells. Cell transdifferentiation has been recognized as one of the mechanisms in chemoresistance. Accordingly, we hypothesized that PAX5 might promote SCLC chemoresistance by inducing a YAP1-mediated cell transdifferentiation program. Therefore, this project will further address the following scientific questions: 1) whether PAX5 induces the transdifferentiation of SCLC cells by upregulating YAP1 expression? 2) whether PAX5 promotes SCLC chemoresistance by regulating YAP1-mediated cell transdifferentiation? Collectively, this study will uncover a key mechanism that regulates chemoresistance in SCLC and provide a potential target for the clinical treatment of SCLC.