Inflammation-induced cellular plasticity in pancreatic homeostasis and tumorigenesis

炎症诱导的胰腺稳态和肿瘤发生中的细胞可塑性

• 批准号: 10314468
• 负责人: David Falvo
• 金额: $ 4.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2024-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314468
• 关键词: 3-Dimensional; Acinar Cell; Address; Caerulein; Cancer Etiology; Cells; Cessation of life; Characteristics; Chromatin; Data; Development; Disease; Duct (organ) structure; Epigenetic Process; Epithelial Cells; Etiology; Exposure to; Gene Expression; Genetic Transcription; Goals; Heterogeneity; Histologic; Homeostasis; In Vitro; Inflammation; Inflammatory; Injury; Lead; Lesion; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Memory; Metaplasia; Molecular; Natural regeneration; Oncogene Activation; Oncogenic; Outcome; Pancreas; Pancreatitis; Pathogenesis; Pathway interactions; Patients; Play; Population; Predisposition; Prevention strategy; Process; Public Health; Recording of previous events; Recovery; Resistance; Resolution; Risk; Risk Factors; Role; Stimulus; Stress; Survival Rate; System; Tissues; Transcription Factor AP-1; United States; Up-Regulation; cancer initiation; cancer prevention; epigenetic memory; experience; genome-wide; high risk; in vivo Model; insight; mouse model; mutant; novel; pancreas development; pancreatic tumorigenesis; patient population; premalignant; restoration; therapeutic development; therapeutic target; therapy design; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY Pancreatic cancer is a near universally fatal disease with a 5-year survival rate of less than 9%. As the third leading cause of cancer-related deaths in the United States, pancreatic cancer is a major public health concern, necessitating significant advances in our understanding of the underlying disease etiologies. Substantial evidence has recognized inflammation’s role in destabilizing tissue homeostasis. In the pancreas, inflammation manifests as a transient cell-fate transition known as acinar-to-ductal metaplasia (ADM), which is known to play varying roles in both tumor initiation and progression. However, much is still to be learned about how ADM and inflammation—even after subsequent resolution—can lead to the accumulation of molecular changes that aid in pancreatic cancer initiation. Interestingly, we have found that following pancreatitis, acinar cells carry chromatin accessibility changes that persist even eighteen-weeks after histologic recovery. Furthermore, we observe that following resolution of pancreatitis, the persisting inflammatory memory synergizes with either a secondary, sub- threshold non-inflammatory stimulus or oncogenic stress to induce either promiscuous ADM induction or pancreatic tumorigenesis, respectively. Acinar cells thus fail to fully differentiate, and maintain a ‘memory’ of the cycle of metaplasia and regeneration, lowering the threshold for dedifferentiation and tumorigenesis. Motif analysis demonstrates the enrichment of AP-1 motifs at these memory regions—a transcriptional effector activated downstream of the Ras/MAPK pathway. In addition, our preliminary data demonstrates that the acinar population responds heterogeneously to inflammation-associated injury—with both an ADM-permissive and an ADM-resistant population co-occurring during pancreatitis. Given these findings, we hypothesize that AP- 1/Fra1 promotes inflammatory memory formation and tumorigenesis in a subset of pancreatic acinar cells permissive to metaplastic transition. In the proposed studies, we set out to determine if AP-1/Fra1 is responsible for memory formation, promiscuous ADM induction, and tumor initiation. Additionally, the proposed studies serve to identify the cellular dynamics associated with metaplastic transition, the distribution of the memory in ADM-permissive and -resistant populations, as well as the increased susceptibility of ADM-permissive cells to malignant transformation. To address the functional role of Fra1, we will utilize complementary 2D/3D in vitro systems and in vivo models of Fra1 deletion and AP-1 inhibition. To determine the molecular characteristics, dynamics, and tumorigenic outcomes associated with the divergent cell fate decisions, we will employ distinct lineage tracing mouse models that conditionally mark cells and reversibly induce mutant Kras in the pancreas. We anticipate that a better understanding of these processes will further elaborate on the connection between inflammation and oncogenesis, as well as provide avenues for the development of therapeutics that mitigate the effects of these cancer-sensitizing states in high-risk patient populations with prior pancreatitis.

项目摘要 胰腺癌是一种几乎普遍致命的疾病，5年生存率小于9％。作为第三 美国与癌症相关死亡的主要原因，胰腺癌是一个主要的公共卫生问题， 我们需要在我们对潜在疾病病因的理解方面取得重大进展。重大的 证据已经认识到炎症在破坏组织稳定稳定的稳定稳定性中的作用。在胰腺中，炎症 表现为一种瞬态细胞命令过渡，称为腺泡到导管变质（ADM），已知可以发挥作用 在肿瘤倡议和进展中的角色不同。但是，关于ADM和 炎症（即使在随后的分辨率之后）也会导致分子变化的积累，以帮助 胰腺癌倡议。有趣的是，我们发现胰腺炎后，腺泡细胞携带染色质 组织学恢复后甚至持续十八周的可访问性变化。此外，我们观察到 分辨胰腺炎后，持续的炎症记忆与次级，亚次级 - 阈值非炎性刺激或致癌应激，以诱导混杂的ADM诱导或 胰腺肿瘤发生。因此，腺泡细胞无法完全区分，并维持对 化生和再生的循环，降低了去分化和肿瘤发生的阈值。主题 分析证明了这些记忆区域的AP-1基序的富集 - 转录效应器 RAS/MAPK途径的下游激活。此外，我们的初步数据表明腺泡 人口反应异构对炎症相关的损伤，既有抗药毒剂又 胰腺炎期间的抗ADM耐药人群。鉴于这些发现，我们假设 1/fra1促进胰腺腺泡子集中的炎症记忆形成和肿瘤发生 细胞允许转移过渡。在拟议的研究中，我们着手确定AP-1/FRA1是否为 负责记忆形成，承诺ADM诱导和肿瘤的启动。另外，提议 研究来确定与化生过渡相关的细胞动力学， 在ADM-允许和抗拒的人群中的记忆，以及ADM验证的易感性提高 细胞进行恶性转化。为了解决FRA1的功能作用，我们将使用完整的2D/3D FRA1缺失和AP-1抑制的体外系统和体内模型。为了确定分子特征， 动力学和与不同细胞脂肪决策相关的肿瘤结局，我们将采用独特的 谱系追踪小鼠模型，该模型有条件地标记细胞并可逆地影响胰腺中的突变体Kras。 我们预计，对这些过程的更好理解将进一步阐述 炎症和肿瘤发生，并为减轻治疗剂的发展提供了途径 这些对癌症敏感状态的影响在先前胰腺炎的高危患者人群中的影响。