Defining the role of chromatin remodeling complexes in pancreatic cancer stem cells

项目摘要 胰腺癌（PDAC）是一种毁灭性的疾病，其特征在于高转移率， 治疗反应差。目前，它是发达国家癌症相关死亡的第四大原因 尽管努力改进治疗，五年生存率仍保持在9%。因此， 确定推动胰腺癌进展和治疗耐药性的新方案。定义新 癌症的依赖性，在Reya实验室的工作集中在表征干细胞程序，驱动癌症 启动、传播和复发。先前发表的研究表明， Musashi 2在功能上标志着胰腺癌的干细胞群，最近的研究表明， 该干细胞群的特征在于高度独特的转录和表观遗传谱。鉴于 表观遗传调节在癌症发展和失调中的重要作用，这是合乎逻辑的假设 差异表达的表观遗传调节因子可能是建立或 维持胰腺癌中这种独特的干细胞状态。使用功能屏幕来描述影响 在体外对干细胞的候选表观遗传因子的抑制中，基因Smarcd 3已被鉴定为一种抑制因子。 胰腺癌干细胞生长的潜在关键介质。Smarcd 3编码Baf 60 c，Baf 60 c是 SWI/SNF核小体重塑复合物，已知其在胰腺癌中失调。 初步研究表明，Smarcd 3抑制导致KPf/fC胰腺癌生长减少 干细胞在体外和体内。Smarcd 3抑制也导致减少的锚定非依赖性生长， 人胰腺癌细胞系的体外研究。根据这些数据，本提案的目的是测试 （1）Smarcd 3是胰腺癌生长和干细胞扩增所必需的， （2）Smarcd 3是人胰腺癌细胞系生长所必需的， 患者来源的胰腺癌异种移植物。

Project Summary Pancreatic adenocarcinoma (PDAC) is a devastating disease characterized by high rates of metastasis and poor therapeutic response. It is currently the 4th leading cause of cancer related deaths in developed countries and despite efforts to improve therapy, the five-year survival rate remains at 9%. Therefore it is critical to identify new programs that drive pancreatic cancer progression and therapeutic resistance. To define new cancer dependencies, work in the Reya lab has focused on characterizing stem cell programs that drive cancer initiation, propagation, and relapse. Previously published studies have demonstrated that the fate determinant Musashi2 functionally marks a stem population in pancreatic cancer, and more recent work has revealed that this stem cell population is characterized by a highly unique transcriptional and epigenetic profile. Given the crucial role for epigenetic regulation in development and dysregulation in cancer, it is logical to hypothesize that differentially expressed epigenetic regulatory factors could be responsible for the establishment or maintenance of this unique stem cell state in pancreatic cancer. Using functional screens to profile the impact of inhibition of candidate epigenetic factors on stem cells in vitro, the gene Smarcd3 has been identified as a potential critical mediator of stem cell growth in pancreatic cancer. Smarcd3 encodes Baf60c, a component of the SWI/SNF nucleosome remodeling complex that is known to be dysregulated in pancreatic cancer. Preliminary studies have shown that Smarcd3 inhibition leads to reduced growth of KPf/fC pancreatic cancer stem cells in vitro and in vivo. Smarcd3 inhibition also leads to reduced anchorage-independent growth of human pancreatic cancer cell lines in vitro. Based on these data, the aims of this proposal are to test the hypotheses that (1) Smarcd3 is required for pancreatic cancer growth and stem cell expansion in genetically engineered mouse models, and (2) Smarcd3 is required for growth of human pancreatic cancer cell lines and patient-derived pancreatic cancer xenografts.