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

项目摘要 胰腺癌(PDAC)是一种以高转移率和高转移率为特征的破坏性疾病 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，五年存活率仍保持在9%。因此，至关重要的是 确定推动胰腺癌进展和治疗耐药的新方案。要定义新的 癌症依赖性，雷亚实验室的工作重点是表征导致癌症的干细胞程序 开始、繁殖和复发。此前发表的研究表明，命运的决定因素 Musashi2在功能上标记了胰腺癌的干细胞群体，最近的研究表明 这个干细胞群体的特点是高度独特的转录和表观遗传学特征。给定 表观遗传调控在癌症发育和失调中的关键作用，假设是合乎逻辑的 差异表达的表观遗传调控因子可能负责建立或 在胰腺癌中维持这种独特的干细胞状态。使用功能屏幕来描述影响 关于候选表观遗传因子在体外对干细胞的抑制，Smarcd3基因已被鉴定为 胰腺癌干细胞生长的潜在关键介体。Smarcd3编码BAF60c，BAF60c是 已知在胰腺癌中调节失调的SWI/SNF核小体重塑复合体。 初步研究表明，Smarcd3抑制导致KPF/FC胰腺癌生长减少 干细胞在体外和体内。抑制Smarcd3还会导致与锚定无关的生长减少 体外培养人胰腺癌细胞株。基于这些数据，这项提案的目的是测试 假设(1)Smarcd3是胰腺癌生长和干细胞扩增所必需的基因 转基因小鼠模型，以及(2)Smarcd3是人胰腺癌细胞株和 患者来源的胰腺癌异种移植。

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.