The transcriptional and epigenetic landscape of cell fate changes in murine pancreatic cancer initiation and metastasis

项目摘要 胰腺癌是美国第四大致命性癌症，而且还在上升，它代表着 每年诊断的所有癌症病例的3%，但在每年所有癌症死亡人数中不成比例的8% 年。由于缺乏早期症状，胰腺癌倾向于在较晚的时候被诊断出来。 分期，通常是转移后：只有不到20%的患者适合手术切除。 这导致所有阶段的5年平均存活率低得令人沮丧，仅为9% 因此，早期发现和消除的高分辨率方法至关重要。 胰腺导管腺癌(PDAC)是一种胰腺外分泌细胞癌。 胰腺，占每年确诊的胰腺癌病例的93%。发起了 在PDAC之前有一种特征性的细胞命运改变，称为腺泡到导管的化生(ADM)。 ADM是胰腺损伤或炎症过程中自然发生的可逆过程。 然而，在致癌的KRAS基因G12D突变后，ADM后状态不能 反转，促进进展到PDAC前体状态。ADM是由以下变化调节的 转录和表观遗传调控。特别是，多能性因子Klf4一直是 被牵连为ADM的主要监管者。 表观遗传重新编程也被揭示为PDAC的主要驱动因素 进展和转移。最近的一项研究发现全基因组FOXA1介导的增强子 重新编程成为PDAC转移的主要驱动因素。FOXA1和2是先锋因素 已知对胰腺发育也是必要的。此外，基因组规模 组蛋白修饰的重新编程也被证明可以推动从 局部到远处的转移。KLF4和FOXA1等细胞命运相关因子在细胞死亡中的作用 癌症相关转化迫切需要研究胰腺与 细胞命运可塑性、重编程和肿瘤发生。 ADM和PDAC过程中转录组和表观基因组与细胞命运相关的变化 转移还没有得到全面的描述。拟议中的项目利用了 ADM、PDAC和转移的小鼠模型来表征这种关系 细胞特性和肿瘤发生的变化。我们的目标是1)确定转录组和 表观基因组在ADM过程中的变化，以及2)决定表观遗传失调的相似性 在PDAC进展和ADM之间。我们希望这个项目的完成将揭示出新的 PDAC的特性可用于潜在的早期检测和治疗靶向。

Project Summary Pancreatic cancer, the fourth most lethal cancer in the United States and rising, represents 3% of all cancer cases diagnosed per year but a disproportionate 8% of all cancer deaths per year. Because of a lack of early symptoms, pancreatic cancer tends to be diagnosed in later stages, often post-metastasis: fewer than 20% of patients are candidates for surgical resection. This contributes to a dismally low average 5-year survival rate of 9% across all stages at diagnosis; thus, higher resolution methods for early detection and abrogation are crucial. Pancreatic ductal adenocarcinoma (PDAC), a cancer of the exocrine cells of the pancreas, represents 93% of pancreatic cancer cases diagnosed per year. The initiation of PDAC is preceded by a characteristic cell fate change called acinar-to-ductal metaplasia (ADM). ADM is a naturally occurring, reversible process during pancreatic injury or inflammation. However, upon an oncogenic G12D mutation of the KRAS gene, a post-ADM state cannot be reversed, facilitating progression to a PDAC precursor state. ADM is mediated by changes in transcriptional and epigenetic regulation. In particular, the pluripotency factor Klf4 has been implicated as a master regulator of ADM. Epigenetic reprogramming has also been revealed as a major driver of PDAC progression and metastasis. A recent study found genome-wide Foxa1-mediated enhancer reprogramming to be a major driver of PDAC metastasis. Foxa1 and 2 are pioneer factors are known also to be necessary for pancreatic development. Furthermore, genome-scale reprogramming of histone modifications has also been demonstrated to drive the transition from local to distant metastasis. The role of cell fate-associated factors such as Klf4 and Foxa1 in cancer-associated transformations urges investigation of the relationship between pancreatic cell fate plasticity, reprogramming, and oncogenesis. Cell fate-related changes in the transcriptome and epigenome during ADM and PDAC metastasis have not been comprehensively profiled. The proposed project takes advantage of murine models of ADM, PDAC, and metastasis to characterize this relationship between changes in cell identity and oncogenesis. We aim to 1) determine how the transcriptome and epigenome change during ADM, and 2) determine the parallels in epigenetic dysregulation between PDAC progression and ADM. We hope that completion of this project will reveal novel properties of PDAC for potential early detection and therapeutic targeting.