Dissecting the oncogenic and pro-metastatic roles of PTHLH-mediated calcium signaling in pancreatic cancer

剖析 PTHLH 介导的钙信号传导在胰腺癌中的致癌和促转移作用

• 批准号: 10441551
• 负责人: Jason R. Pitarresi
• 金额: $ 13.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441551
• 关键词: 3-Dimensional; Accounting; Advisory Committees; Antibodies; Attenuated; Automobile Driving; Award; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Signaling; Cancer Etiology; Cause of Death; Cell Proliferation; Cells; Cessation of life; Clinical; Clinical Management; Code; Development Plans; Disease; Disease Management; E-Cadherin; Early Diagnosis; Epithelial; Epithelial Cells; Esophagus; Event; Faculty; Family; Foundations; Funding; Gene Expression Profiling; Genes; Genetic; Genetically Engineered Mouse; Goals; Grant; Health; Human; Immune; Immune Evasion; Immunotherapeutic agent; Immunotherapy; KRASG12D; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentors; Mitochondria; Mus; Myeloid-derived suppressor cells; Neoplasm Metastasis; Neoplastic Cell Transformation; Null Lymphocytes; Oncogenes; Oncogenic; Organoids; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patients; Phase; Phenotype; Play; Primary Neoplasm; Process; Prognosis; Proteins; Research; Role; Signal Pathway; Signal Transduction; Solid; Squamous cell carcinoma; Stains; Survival Rate; System; Testing; Training; Transplantation; Tumor Suppressor Genes; Tumor-infiltrating immune cells; United States National Institutes of Health; Work; calcium uniporter; calcium-dependent protein kinase; career; career development; catenin p120ctn protein; cell motility; cohort; detection method; efficacy evaluation; efficacy testing; epithelial to mesenchymal transition; experimental study; hormone therapy; improved; member; mouse model; neoplastic cell; neutralizing antibody; neutralizing monoclonal antibodies; novel; novel strategies; novel therapeutics; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic tumorigenesis; parathyroid hormone-related protein; preclinical trial; recruit; research and development; skills; therapeutic target; tumor; tumor growth; tumor-immune system interactions

PROJECT SUMMARY Pancreatic cancer is a major health issue in the US, with only 7% of patients surviving beyond 5 years and nearly all patients presenting with metastases. Identifying factors that increase metastasis may aid early detection methods and discover therapeutically targetable pathways to help with the clinical management of this disease. To this end, we have generated a mouse model to delete the Ctnnd1 gene (which codes for the protein p120catenin or p120ctn), which is necessary for E-CADHERIN stability and whose deletion results in enhanced epithelial-to-mesenchymal transition (EMT) and metastasis in the Pdx-cre; KrasG12D; p53f/f (KPC) pancreatic cancer mouse model. We show that KPC-p120ctnKO mice have dramatically enhanced metastatic burden relative to control littermates. An unbiased screen of tumor cells from these mice resulted in the identification of misregulated calcium signaling through the secreted factor Parathyroid Hormone Like Hormone (PTHLH) as a previously unappreciated contributor of EMT/metastasis. Importantly, Pthlh deletion in orthotopic transplantation experiments showed significantly reduced tumor growth and metastasis, suggesting PTHLH as an oncogenic and pro-metastatic factor. Furthermore, treatment with an anti-PTHLH monoclonal neutralizing antibody reduced cell proliferation and migration, demonstrating a potential clinical benefit. Finally, we have generated a preliminary cohort of KPC-PthlhKO mice that have increased survival relative to KPC controls and are currently embarking on a preclinical trial with anti-PTHLH antibody in KPC mice, to determine if blocking PTHLH will attenuate this disease. Thus, we hypothesize that PTHLH is a driver of pancreatic tumorigenesis and metastasis. This will be achieved through the following interrelated Specific Aims: Aims 1 and 2 are to define the effect of Pthlh deletion or inhibition upon pancreatic epithelial cell identity and ultimately, metastatic colonization. In the same context, we will explore the role that other regulators (Camk2b and Mcu) of calcium signaling (Aim 3) play in these processes and identify novel downstream signaling components involved in calcium-mediated pancreatic cancer metastases. Finally, in Aim 4, we will determine the role of PTHLH in orchestrating the immune microenvironment and co-treat with immunotherapy. The proposed training in this K99-R00 application outlines an integrated plan of mentored research and career development activities, as well as a specific strategy for my pathway to an independent research career in pancreatic cancer. This award will allow me to refine existing and gain additional skills with the guidance of my research mentors, Drs. Stanger and Rustgi, as well as an interdisciplinary advisory committee. Taken together, the scientific proposal and training/career development plans will provide a compelling foundation for me to become eventually a successful independent NIH funded faculty member.

项目摘要 胰腺癌是美国的主要健康问题，只有7％的患者生存超过5年 几乎所有出现转移的患者。识别增加转移的因素可能会提早有助于 检测方法并发现具有治疗目标的途径，以帮助进行临床管理 疾病。为此，我们生成了一个鼠标模型来删除CTNND1基因（该基因编码为蛋白质 P120卡宁或P120CTN），这对于e-钙粘蛋白稳定性是必需的，其缺失导致增强 PDX-CRE中的上皮到间质转变（EMT）和转移； krasg12d; p53f/f（KPC）胰腺 癌小鼠模型。我们表明，KPC-P120CTNKO小鼠具有显着增强的转移负担 控制同窝仔。这些小鼠的肿瘤细胞的无偏筛网导致鉴定 通过分泌因子甲状旁腺激素（如激素（PTHLH））作为一种钙信号传导误导 EMT/转移的先前未欣赏的贡献者。重要的是，原位移植中的PTHLH缺失 实验显示肿瘤的生长和转移显着降低，表明PTHLH是一种致癌 和促近转移因子。此外，用抗PTHLH单克隆中和抗体的治疗降低 细胞增殖和迁移，表明潜在的临床益处。最后，我们已经产生了 相对于KPC对照的生存率增加的KPC-PTHLHKO小鼠的初步队列 在KPC小鼠中使用抗PTHLH抗体进行临床前试验，以确定阻塞PTHLH是否会 减弱这种疾病。因此，我们假设PTHLH是胰腺肿瘤发生和转移的驱动力。 这将通过以下相互关联的特定目的来实现：目标1和2是定义 PTHLH缺失或抑制对胰腺上皮细胞身份的影响，最终是转移性定殖。 在同一情况下，我们将探讨其他调节剂（CAMK2B和MCU）钙信号传导的作用（AIM 3）在这些过程中播放并识别参与钙介导的新型下游信号传导成分 胰腺癌转移。最后，在AIM 4中，我们将确定PTHLH在策划免疫中的作用 微环境和与免疫疗法共同治疗。 该K99-R00应用程序的拟议培训概述了指导研究的综合计划和 职业发展活动以及我通往独立研究职业途径的特定策略 在胰腺癌中。该奖项将使我能够在指导下完善现有并获得其他技能 我的研究导师，博士。 Stanger和Rustgi，以及跨学科咨询委员会。拍摄 科学建议和培训/职业发展计划一起将为 我最终成为成功的独立NIH资助的教职员工。

项目成果

Pancreatic plasticity: Unlocking exocrine lineage specification.

胰腺可塑性：解锁外分泌谱系规范。

• DOI: 10.1016/j.stem.2021.05.006
• 发表时间: 2021
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Pitarresi,JasonR;Rustgi,AnilK
• 通讯作者: Rustgi,AnilK

Growth of pancreatic cancers with hemizygous chromosomal 17p loss of MYBBP1A can be preferentially targeted by PARP inhibitors.

• DOI: 10.1126/sciadv.abc4517
• 发表时间: 2020-12
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Hsieh A;Pitarresi JR;Lerner J;Donahue G;Hsiehchen D;Rustgi AK;Zaret K
• 通讯作者: Zaret K

Single-cell analysis of ductal differentiation.

导管分化的单细胞分析。

• DOI: 10.1038/s41551-021-00782-1
• 发表时间: 2021
• 期刊: Nature biomedical engineering
• 影响因子: 28.1
• 作者: Pitarresi,JasonR;Rustgi,AnilK
• 通讯作者: Rustgi,AnilK