Investigating Cellular Communication in the Tumor Microenvironment in Pancreatic Cancer

研究胰腺癌肿瘤微环境中的细胞通讯

• 批准号: 10284422
• 负责人: Nina G Steele
• 金额: $ 13.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 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 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284422
• 关键词: Address; Advisory Committees; Angiogenic Factor; Award; Behavior; Biology; Blood Vessels; Cancer Biology; Cancer Control; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical Trials; Coculture Techniques; Collaborations; Communication; Complex; Cre driver; Data; Development; Development Plans; Disease; Endothelial Cells; Endothelium; Epithelial; Erinaceidae; Fibroblasts; Fibrosis; Future; Gene Expression; Genes; Genetic study; Goals; Human; Immune; Immune Targeting; Immune response; Immunology; Immunosuppression; Individual; Infiltration; Inflammatory; International; Investigation; Laboratories; Laboratory Research; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentors; Mentorship; Michigan; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pericytes; Pharmacology Study; Phase; Play; Population; Population Heterogeneity; Reaction; Research; Role; SHH gene; Signal Transduction; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tumor Angiogenesis; Tumor-Derived; Universities; Vascularization; Work; angiogenesis; base; career development; dosage; effective therapy; experimental study; gene function; immunoregulation; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; novel; novel strategies; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; paracrine; patient response; receptor; relating to nervous system; response; skills; smoothened signaling pathway; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is projected to become the 2nd leading cause of cancer-related deaths world-wide by 2030, largely due a lack of effective treatments. A major barrier to successful therapy is the abundant fibrotic reaction in PDA, which includes cancer-associated fibroblasts (CAFs). While many pancreatic tumors are hypovascularized, endothelial cells regulate immune maturation and infiltration, tumor cell metabolism, and metastatic dissemination. In PDA, Hedgehog (HH) signaling functions in a paracrine manner, whereby tumor cells produce HH ligands and signal to CAFs via the canonical HH receptor PTCH1, leading to downstream pathway activation. There have been contradictory genetic and pharmacologic studies in mouse models, as well as disappointing clinical trials with HH pathway inhibitors, indicating the role of HH signaling in PDA is highly complex and context dependent. This proposal aims to uncover two key aspects of HH signaling in PDA: a) HH-dependent alterations in the immune landscape through fibroblast-immune cross talk (Aim 1), and b) HH-dependent changes in endothelial cell gene expression and function through fibroblast-endothelial cross talk (Aim 2). I hypothesize that combined targeting of HH signaling in combination with the immune response or the vasculature will be required to effectively treat PDA. Our preliminary data indicate that Slit2, which regulates angiogenesis, is reduced during HH pathway inhibition in PDA. Previous work showed that epithelial Slit2 deletion promotes neural invasion and metastasis in PDA. However, I find the majority of Slit2 is produced by fibroblasts, while Robo receptors are expressed in endothelial cells. In Aim 3 of this proposal, I will determine the fibroblast-specific contribution of Slit2 to pancreatic angiogenesis and tumor growth. Overall, the proposed experiments will provide a fundamentally new understanding of cellular cross talk within the pancreatic TME, including addressing fibroblast-immune and fibroblast-endothelial communication as well as a specific investigation of SLIT-ROBO signaling in pancreatic cancer. The mentored phase of this award will be overseen by Drs. Allen and Pasca di Magliano at the University of Michigan (UM). I have developed an additional advisory team to include internationally known leaders in the fields of cancer biology (Dr. Andrzej Dlugosz), endothelial biology (Dr. Jason Spence), and immunology (Dr. Bethany Moore). Combined, this mentorship team has set forth a career development plan focused on research, collaboration, presentations, mentorship, grantsmanship, and the furthering of management skills required to successfully lead an independent research laboratory.

项目摘要/摘要 胰腺导管腺癌（PDA）预计将成为与癌症相关死亡的第二大原因 到2030年，全球范围内，主要是由于缺乏有效的治疗方法。成功治疗的主要障碍是 PDA中丰富的纤维化反应，其中包括与癌症相关的成纤维细胞（CAF）。而许多胰腺 肿瘤是无血管内的，内皮细胞调节免疫成熟和浸润，肿瘤细胞 代谢和转移性传播。在PDA中，刺猬（HH）信号传导以旁分泌的方式函数， 肿瘤细胞通过规范的HH受体PTCH1产生HH配体并向CAF发出信号，导致 下游途径激活。小鼠有矛盾的遗传和药理研究 模型，以及HH途径抑制剂的临床试验令人失望，表明HH信号在 PDA非常复杂，背景依赖。该建议旨在发现HH信号的两个关键方面 在PDA中：a）通过成纤维细胞 - 免疫串扰（AIM 1）， b）内皮细胞基因表达和通过成纤维细胞内皮的功能的HH依赖性变化 交谈（目标2）。我假设HH信号与免疫结合的组合靶向 反应或脉管系统将需要有效治疗PDA。我们的初步数据表明slit2， 调节血管生成，在PDA中HH途径抑制期间降低。以前的工作表明 上皮裂隙2缺失可促进PDA中的神经侵袭和转移。但是，我发现大多数slit2是 由成纤维细胞产生，而机器人受体在内皮细胞中表达。在本提案的目标3中，我将 确定Slit2对胰腺血管生成和肿瘤生长的成纤维细胞特异性贡献。总体而言， 拟议的实验将对内部的细胞交叉讲座提供新的理解 胰腺TME，包括解决成纤维细胞 - 免疫和成纤维细胞 - 内皮通信 以及对胰腺癌缝隙 - 摩托 - 罗伯信号传导的特定研究。这是这一指导阶段 奖项将由Drs监督。密歇根大学（UM）的Allen和Pasca di Magliano。我已经开发了 一个额外的咨询团队，包括癌症生物学领域的国际知名领导者（Andrzej博士 Dlugosz），内皮生物学（Jason Spence博士）和免疫学（Bethany Moore博士）。合并，这个 指导团队制定了一项职业发展计划，重点是研究，协作，演讲， 指导，授予技巧以及成功领导的管理技能的进一步 独立研究实验室。