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

小鼠胰腺癌发生和转移中细胞命运变化的转录和表观遗传景观

• 批准号: 10397987
• 负责人: Emily Lo
• 金额: $ 4.68万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397987
• 关键词: Acinar Cell; Cell Fate Control; Cells; Cessation of life; Characteristics; Chromatin Structure; DNA; DNA Methylation; Detection; Development; Diagnosis; Disease; Distant Metastasis; Duct (organ) structure; Early Diagnosis; Ectopic Expression; Enhancers; Epigenetic Process; Event; Excision; Future; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Inflammation; Inflammatory; Investigation; KRAS2 Gene Mutation; KRASG12D; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Metaplasia; Methods; Modeling; Modification; Movement; Mus; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Patients; Primary Neoplasm; Process; Property; Research; Resolution; Role; Stage at Diagnosis; Survival Rate; Symptoms; Therapeutic; Transcriptional Regulation; United States; Work; cancer initiation; cancer predisposition; cancer stem cell; carcinogenesis; combat; detection method; epigenetic regulation; epigenome; genome-wide; histone modification; methylomics; mouse model; neoplastic; novel; pancreas development; pancreatic ductal adenocarcinoma model; pluripotency; pluripotency factor; progenitor; stem cells; targeted treatment; therapeutic target; transcription factor; transcriptome; transcriptomics; tumor; tumorigenesis

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.

项目摘要 胰腺癌是美国第四大致死性癌症，而且还在上升， 每年诊断出的所有癌症病例的3%，但每年所有癌症死亡的8%不成比例。 年由于缺乏早期症状，胰腺癌往往在较晚的时候被诊断出来。 阶段，通常是转移后：不到20%的患者是手术切除的候选人。 这导致所有阶段的平均5年生存率极低，仅为9%， 因此，早期发现和消除的更高分辨率方法至关重要。 胰腺导管腺癌（PDAC），一种胰腺外分泌细胞的癌症， 胰腺癌占每年诊断的胰腺癌病例的93%。启动 PDAC之前是一个特征性的细胞命运的变化，称为腺泡到导管化生（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KRAS基因的致癌性G12D突变时，ADM后状态不能被逆转。 逆转，促进进展到PDAC前体状态。ADM是通过改变 转录和表观遗传调控。特别地，多能性因子Klf4已经被证实是多能性因子Klf4。 被认为是ADM的主要调节者。 表观遗传重编程也被揭示为PDAC的主要驱动力 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 重编程是PDAC转移的主要驱动因素。Foxa1和Foxa2是先锋因子， 也是胰腺发育所必需的。此外，基因组规模 组蛋白修饰的重编程也被证明可以驱动从 局部到远处转移。细胞命运相关因子如Klf4和Foxa1在 癌症相关的转化促使人们研究胰腺癌与癌症之间的关系， 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的细胞命运相关变化 转移尚未得到全面的描述。拟议项目利用 ADM、PDAC和转移的小鼠模型，以表征ADM和PDAC之间的关系。 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 ADM过程中表观基因组的变化，以及2）确定表观遗传失调的平行关系 之间的PDAC进展和ADM。我们希望这个项目的完成将揭示新的 PDAC具有潜在的早期检测和治疗靶向的特性。

项目成果

Platform-agnostic CellNet enables cross-study analysis of cell fate engineering protocols.

• DOI: 10.1016/j.stemcr.2023.06.008
• 发表时间: 2023-08-08
• 期刊: STEM CELL REPORTS
• 影响因子: 5.9
• 作者: Lo, Emily K. W.;Velazquez, Jeremy J.;Peng, Da;Kwon, Chulan;Ebrahimkhani, Mo R.;Cahan, Patrick
• 通讯作者: Cahan, Patrick