The Pancreatic Cancer Microenvironment

胰腺癌微环境

基本信息

批准号：
10675422
负责人：
Rui Kang
金额：
$ 36.62万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10675422
关键词：
ATM Gene Mutation ATM deficient Ablation Acceleration Affect Alzheimer&apos s Disease Animal Genetics Animal Model Animals Autophagocytosis Biology CD8-Positive T-Lymphocytes Cell Death Cells Clinical Clinical Oncology Clinical Research Clinical Trials Combination Drug Therapy Data Development Disease Disease Progression Distant Metastasis Drug resistance Energy Metabolism FPS-FES Oncogene Frequencies Functional disorder Future Genetic Genetically Engineered Mouse Goals Growth HIF1A gene HMGB1 gene Heterozygote Human Hypoxia Immune Immune checkpoint inhibitor Immuno-Chemotherapy Immunophenotyping Immunotherapy In Vitro Infection Inflammation Inflammatory Response Intervention KRAS2 gene Knock-out Knockout Mice Malignant Neoplasms Malignant neoplasm of pancreas Mediating Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Myeloid-derived suppressor cells Natural History Neoplasm Metastasis Neoplasms Nuclear Nuclear Receptors Oncogenes Oncogenic Paclitaxel Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Pattern recognition receptor Phenotype Play Production Proliferating Receptor Inhibition Regulatory T-Lymphocyte Research Resistance Role Signal Transduction Sterility T cell response T-Lymphocyte TLR4 gene Testing Tissues Work Xenograft Model Xenograft procedure anti-PD-L1 anti-tumor immune response anticancer activity ataxia telangiectasia mutated protein attenuation cancer cell cancer invasiveness cancer therapy chemotherapy clinically relevant conditional knockout gemcitabine immune cell infiltrate improved in vivo inhibitor insight migration mouse model neoplastic cell neutralizing antibody novel novel therapeutic intervention novel therapeutics overexpression pancreatic ductal adenocarcinoma cell pancreatic neoplasm pancreatic tumorigenesis pharmacologic prevent receptor for advanced glycation endproducts subcutaneous therapeutic target transcription factor treatment response tumor tumor initiation tumor microenvironment tumor-immune system interactions

项目摘要

Abstract The tumor microenvironment (TME) is recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escape, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of sterile inflammation and infection. We recently demonstrated that RAGE plays a unique oncogenetic role in pancreatic ductal adenocarcinoma (PDAC). We demonstrated that: 1) RAGE was highly expressed in mouse and human PDAC; 2) Global ablation of RAGE in mice prevented pancreatic cancer growth in a genetically-modified spontaneous mouse model (Pdx1-Cre;K-RasG12D/+;RAGE-/-) and a xenograft mouse model; 3) RAGE was essential for oncogenic K-Ras-mediated hypoxic signaling in PDAC development; and 4) The mechanism by which this occurs in part involves inflammatory response-associated metabolic changes, cell death-promoting limitations in autophagy, and a reduction in the accumulation of myeloid-derived suppressor cells and regulatory T cells. These exciting findings raise several important questions regarding RAGE's novel role in PDAC. We hypothesize that RAGE expression in multiple components of the TME is critical for PDAC development and therapy resistance. We will pursue the following aims. Aim 1: identify RAGE as a critical receptor of nuclear danger signal in the TME; Aim 2: define the cell-specific role of RAGE in the TME; and Aim 3: investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in different tumor models in mice. The completion of these exciting studies will provide new insights into our understanding of the TME and guide future development of RAGE-based novel therapeutic strategies for PDAC patients.

抽象的肿瘤微环境（TME）被认为是疾病进展的多个阶段的关键因素，尤其是局部抵抗，免疫扫描和遥远的转移，从而实质上影响了未来开发临床肿瘤学方面干预措施。晚期糖基终产物的受体（RAGE）是一种模式识别受体，主要参与内源分子的识别在无菌炎症和感染的背景下释放。我们最近证明愤怒发挥了独特的作用在胰腺导管腺癌（PDAC）中的致癌作用。我们证明：1）愤怒很高用小鼠和人类PDAC表示； 2）小鼠愤怒的全球消融阻止了胰腺癌的生长在遗传改性的自发小鼠模型中模型; 3）愤怒对于PDAC发育中的致癌K-RAS介导的低氧信号传导至关重要；和4）这种机制部分发生的机制涉及炎症反应相关的代谢变化，细胞自噬的促进死亡的限制，并减少了髓样衍生的抑制器的积累细胞和调节性T细胞。这些令人兴奋的发现引发了有关Rage小说的几个重要问题在PDAC中的作用。我们假设TME多个组件中的愤怒表达对于PDAC至关重要开发和耐药性。我们将追求以下目标。目标1：确定愤怒是关键 TME中核危险信号的受体；目标2：定义愤怒在TME中的细胞特异性作用；和目标 3：研究愤怒抑制剂与化学免疫疗法的抗肿瘤功效小鼠肿瘤模型。这些令人兴奋的研究的完成将为我们的理解提供新的见解 TME并指导基于愤怒的PDAC患者的新型治疗策略的未来发展。