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
基本信息
- 批准号:10696155
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccountingAdvisory CommitteesAntibodiesAttenuatedAutomobile DrivingAwardCa(2+)-Calmodulin Dependent Protein KinaseCalciumCalcium SignalingCancer EtiologyCause of DeathCell ProliferationCellsCessation of lifeClinicalClinical ManagementCodeCytoplasmDevelopment PlansDiseaseDisease ManagementEarly DiagnosisEpithelial CellsEpitheliumEsophagusEventFacultyFamilyFoundationsFundingGene Expression ProfilingGenesGeneticGenetically Engineered MouseGoalsGrantHealthHumanImmuneImmune EvasionImmunotherapeutic agentImmunotherapyKPC modelKRASG12DLigandsMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMentorsMitochondriaMusMyeloid-derived suppressor cellsNeoplasm MetastasisNeoplastic Cell TransformationNull LymphocytesOncogenesOncogenicOrganoidsPancreasPancreatic Ductal AdenocarcinomaPathogenesisPathway interactionsPatientsPhasePhenotypePlayPrimary NeoplasmProcessPrognosisProteinsResearchRoleSignal PathwaySignal TransductionSolidSquamous cell carcinomaStainsSurvival RateSystemTestingTherapeutically TargetableTrainingTransplantationTumor Suppressor GenesTumor-infiltrating immune cellsUnited States National Institutes of HealthWorkcalcium uniportercalcium-dependent protein kinasecareercareer developmentcatenin p120ctn proteincell motilitycohortdetection methodefficacy evaluationefficacy testingepithelial to mesenchymal transitionexperimental studyhormone therapyimprovedmembermouse modelneoplastic cellneutralizing antibodyneutralizing monoclonal antibodiesnovelnovel strategiesnovel therapeuticspancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpancreatic tumorigenesisparathyroid hormone-related proteinpreclinical trialrecruitresearch and developmentskillstumortumor growthtumor-immune system interactions
项目摘要
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
胰腺癌在美国是一个主要的健康问题,只有7%的患者存活超过5年。
并且几乎所有患者都表现出转移。识别增加转移的因素可能有助于早期
检测方法和发现治疗靶向途径,以帮助临床管理这一点,
疾病为此,我们建立了一个小鼠模型,删除Ctnnd 1基因(编码蛋白质
p120 catenin或p120 ctn),其对于E-CADHERIN稳定性是必需的,并且其缺失导致增强的
Pdx-cre; KrasG 12 D; p53 f/f(KPC)胰腺癌中的上皮-间质转化(EMT)和转移
癌症小鼠模型。我们发现KPC-p120 ctnKO小鼠的转移负荷相对于
来控制同窝仔对来自这些小鼠的肿瘤细胞进行无偏筛选,
通过分泌因子甲状旁腺激素样激素(PTHLH)作为钙信号传导的失调,
以前未被认识到的EMT/转移的贡献者。重要的是,原位移植中的Pthlh缺失
实验显示显著降低肿瘤生长和转移,表明PTHLH是一种致癌因子,
和促转移因子。此外,用抗PTHLH单克隆中和抗体治疗降低了
细胞增殖和迁移,证明了潜在的临床益处。最后,我们生成了一个
KPC-PthlhKO小鼠的初步队列,其相对于KPC对照具有增加的存活率,并且目前
在KPC小鼠中进行抗PTHLH抗体的临床前试验,以确定阻断PTHLH是否会
减轻这种疾病。因此,我们假设PTHLH是胰腺肿瘤发生和转移的驱动因素。
这将通过以下相互关联的具体目标来实现:目标1和目标2是确定
Pthlh缺失或抑制对胰腺上皮细胞特性和最终转移性定殖的影响。
在同样的背景下,我们将探讨钙信号(Aim)的其他调节剂(Camk 2b和Mcu)的作用,
3)在这些过程中发挥作用,并确定新的下游信号转导成分参与钙介导的
胰腺癌转移最后,在目标4中,我们将确定PTHLH在协调免疫过程中的作用。
微环境和免疫治疗的共同治疗。
本K99-R 00应用程序中的拟议培训概述了指导研究的综合计划,
职业发展活动,以及我通往独立研究生涯的具体策略
在胰腺癌中。这个奖项将使我能够完善现有的和获得额外的技能的指导下,
我的研究导师,斯坦格博士和鲁斯特吉博士,以及一个跨学科的咨询委员会。采取
科学建议和培训/职业发展计划将为以下方面提供令人信服的基础:
我最终成为一名成功的独立NIH资助的教师。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jason R. Pitarresi其他文献
Fr332 MUTANT <em>KRAS</em> DRIVEN ACINAR-TO-DUCTAL METAPLASIA IS REGULATED BY <em>FRA1</em>
- DOI:
10.1016/s0016-5085(21)01430-x - 发表时间:
2021-05-01 - 期刊:
- 影响因子:
- 作者:
Jason R. Pitarresi;Rohit Chandwani;Anil Rustgi - 通讯作者:
Anil Rustgi
182 COLLATERAL AMPLIFICATION OF THE PTHRP GENE DRIVES PANCREATIC CANCER GROWTH AND METASTASIS AND REVEALS A THERAPEUTIC VULNERABILITY
- DOI:
10.1016/s0016-5085(21)00853-2 - 发表时间:
2021-05-01 - 期刊:
- 影响因子:
- 作者:
Jason R. Pitarresi;Robert Norgard;Anna Chiarella;Richard Kremer;Ben Z. Stanger;Anil Rustgi - 通讯作者:
Anil Rustgi
FRA1 controls acinar cell plasticity during murine <em>Kras</em><sup><em>G12D</em></sup>-induced pancreatic acinar to ductal metaplasia
- DOI:
10.1016/j.devcel.2024.07.021 - 发表时间:
2024-11-18 - 期刊:
- 影响因子:
- 作者:
Alina L. Li;Kensuke Sugiura;Noriyuki Nishiwaki;Kensuke Suzuki;Dorsay Sadeghian;Jun Zhao;Anirban Maitra;David Falvo;Rohit Chandwani;Jason R. Pitarresi;Peter A. Sims;Anil K. Rustgi - 通讯作者:
Anil K. Rustgi
The 2022 generation.
2022 年的一代。
- DOI:
10.1038/s43018-022-00481-z - 发表时间:
2022 - 期刊:
- 影响因子:22.7
- 作者:
Mautin Barry;Jian Carrot;T. Dayton;S. Ghazanfar;Lillian M. Guenther;Diu T. T. Nguyen;Jason R. Pitarresi;Sheerien Rajput;Naiara Santana;T. Shree;Zexian Zeng;Ying Zhang - 通讯作者:
Ying Zhang
254: COLLATERAL AMPLIFICATION OF THE emKRAS/em LINKED GENE emPTHLH/em GOVERNS PANCREATIC CANCER GROWTH AND METASTASIS AND REVEALS A NEW THERAPEUTIC VULNERABILITY
- DOI:
10.1016/s0016-5085(22)60134-3 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:25.100
- 作者:
Jason R. Pitarresi;Robert Norgard;Anna Chiarella;Kensuke Suzuki;Richard Kremer;Ben Z. Stanger;Anil Rustgi - 通讯作者:
Anil Rustgi
Jason R. Pitarresi的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Jason R. Pitarresi', 18)}}的其他基金
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:
10301700 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
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:
10659332 - 财政年份:2021
- 资助金额:
$ 24.9万 - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Standard Grant
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
$ 24.9万 - 项目类别: