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: 10667444
• 负责人: David Falvo
• 金额: $ 1.97万
• 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 2023-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667444
• 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; Learning; Lesion; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator; Memory; Metaplasia; Molecular; Natural regeneration; Neoplasms; 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; Tumor Promotion; United States; Up-Regulation; cancer initiation; cancer prevention; epigenetic memory; experience; genome-wide; high risk; in vivo Model; insight; mouse model; mutant; neoplastic; novel; pancreas development; pancreatic tumorigenesis; patient population; permissiveness; premalignant; restoration; synergism; 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.

项目概要 胰腺癌是一种几乎普遍致命的疾病，其5年生存率低于9%，位居第三。 胰腺癌是美国癌症相关死亡的主要原因，是一个主要的公共卫生问题， 需要我们对潜在疾病病因的理解取得重大进展。 有证据表明炎症在破坏胰腺组织稳态方面发挥着重要作用。 表现为一种短暂的细胞命运转变，称为腺泡到导管化生 (ADM)，已知其作用 然而，ADM 和进展如何发挥不同的作用仍有待了解。 炎症——即使在随后的解决之后——也会导致分子变化的积累，从而有助于 胰腺癌的发生，我们发现胰腺炎后，腺泡细胞携带染色质。 可达性变化甚至在组织学恢复后持续十八周。此外，我们观察到这一点。 胰腺炎消退后，持续存在的炎症记忆与继发性、亚 阈值非炎症刺激或致癌应激，以诱导混杂的 ADM 诱导或 因此，腺泡细胞无法完全分化并维持“记忆”。 化生和再生周期，降低去分化和肿瘤发生的阈值。 分析表明 AP-1 基序在这些记忆区域中富集——转录效应子 此外，我们的初步数据表明，腺泡在 Ras/MAPK 通路下游被激活。 人群对炎症相关损伤的反应存在差异——ADM 许可型和 ADM 型型均有不同程度的反应。 鉴于这些发现，ADM 耐药人群在胰腺炎期间同时出现。 1/Fra1 促进胰腺腺泡亚群的炎症记忆形成和肿瘤发生 在拟议的研究中，我们着手确定 AP-1/Fra1 是否是允许化生转化的细胞。 负责记忆形成、混杂 ADM 诱导和肿瘤发生。 研究旨在确定与化生转变相关的细胞动力学， ADM 允许和抵抗人群的记忆力，以及 ADM 允许人群的易感性增加 为了解决 Fra1 的功能作用，我们将利用互补的 2D/3D Fra1 缺失和 AP-1 抑制的体外系统和体内模型 确定分子特征， 动力学，以及与不同细胞命运决定相关的致瘤结果，我们将采用不同的 谱系追踪小鼠模型有条件地标记细胞并可逆地诱导胰腺中突变的 Kras。 我们预计，对这些过程的更好理解将进一步阐述之间的联系 炎症和肿瘤发生，并为开发减轻炎症和肿瘤发生的治疗方法提供途径 这些癌症敏感状态对既往患有胰腺炎的高危患者群体的影响。