Project 3 – Stromal derived IL-6/STAT3 signaling in the development and progression of PDAC

项目 3 — PDAC 发生和进展中基质衍生的 IL-6/STAT3 信号传导

• 批准号: 10441214
• 负责人: Michael C. Ostrowski
• 金额: $ 41.51万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441214
• 关键词: Adipocytes; Adipose tissue; Affect; Antibodies; Body Weight decreased; CXCL1 gene; Cachexia; Cell Nucleus; Cells; Communication; Development; Diagnosis; Disease; Extracellular Matrix; Fatigue; Fatty acid glycerol esters; Fibroblasts; Flow Cytometry; Gene Deletion; Genetic; Homeostasis; Human; IL6 gene; Image; Immune; Interleukin-6; Knowledge; L Cells; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mesenchymal; Modeling; Muscle; Muscle satellite cell; Muscular Atrophy; NF-kappa B; Natural regeneration; Operative Surgical Procedures; Paclitaxel; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Radiation therapy; Reaction; Role; STAT3 gene; Sampling; Seminal; Signal Transduction; Skeletal Muscle; Solid Neoplasm; Stat3 Signaling Pathway; Survival Rate; Syndrome; System; Testing; Tissues; Treatment Efficacy; Tumor-infiltrating immune cells; Wasting Syndrome; angiogenesis; cancer cachexia; cytokine; effective therapy; gemcitabine; macrophage; mesenchymal stromal cell; mortality; mouse model; neoplastic cell; pancreas development; pancreatic ductal adenocarcinoma model; programs; recruit; selective attention; single-cell RNA sequencing; targeted treatment; tocilizumab; transcriptome; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; wasting

PROJECT SUMMARY: PROJECT 3 PDAC is among the most deadly malignant solid tumors, with approximately 92% of patients succumbing to the disease within five years of diagnosis, and with no effective therapies beyond surgery. Importantly, it is widely recognized that patients with PDAC are especially prone to cachexia, a syndrome characterized by pronounced weight loss due to depleting skeletal muscle and adipose tissues. As a result, patients are often weak and fatigued, which makes them less tolerant to chemo- and radiotherapy. The histopathological hallmark of PDAC is its uniquely dense stromal reaction, comprised of activated, cancer associated fibroblasts, increased extra- cellular matrix (ECM), immune cell infiltrates, and abnormal angiogenesis. This has engendered attention for selectively targeting the tumor stroma to increase therapeutic efficacy. However, stromal cancer-associated fibroblasts can also have tumor suppressive functions, challenging the efficacy of stromal-targeting therapies. In addition, there is increasing appreciation for the dual role of stromal mesenchymal cells in muscle homeostasis and regeneration, as well as in muscle wasting diseases, including cancer cachexia. Progress in tackling PDAC will require new knowledge of its macroenvironment encompassing crosstalk between the tumor and peripheral tissues. In Project 3, we posit the IL6/STAT3 pathway is a key pathway involved in PDAC macroenvironment cross-talk. Synergistic interactions with the Projects and Cores in this Program Project will allow us to test the hypothesis that STAT3 signaling in stromal mesenchymal cells present in the tumor and muscle is a component of a feed-forward loop in the tumor macroenvironment that favors PDAC progression and cancer cachexia.

项目概要：项目3 PDAC是最致命的恶性实体瘤之一，大约92%的患者死于PDAC。 疾病在五年内诊断，并没有有效的治疗以外的手术。重要的是，它广泛 认识到PDAC患者特别容易发生恶病质，这是一种以明显的 由于消耗骨骼肌和脂肪组织而导致的体重减轻。因此，患者往往身体虚弱， 疲劳，这使得他们对化疗和放疗的耐受性降低。PDAC的组织病理学特征 是其独特的致密基质反应，包括活化的癌相关成纤维细胞，增加的额外- 细胞基质（ECM）、免疫细胞浸润和异常血管生成。这引起了人们的注意， 选择性靶向肿瘤基质以增加治疗功效。然而，基质癌相关的 成纤维细胞还可以具有肿瘤抑制功能，挑战基质靶向疗法的功效。在 此外，越来越多的人认识到间充质细胞在肌肉稳态中的双重作用， 和再生，以及肌肉萎缩性疾病，包括癌症恶病质。处理PDAC的进展 将需要对其宏观环境的新知识，包括肿瘤和外周血管之间的串扰。 组织中在项目3中，我们证实了IL 6/STAT 3通路是PDAC大环境的关键通路， 串话与本计划项目中的项目和核心的协同互动将使我们能够测试 假设肿瘤和肌肉中存在的基质间充质细胞中的STAT 3信号传导是一种组分， 肿瘤宏观环境中的前馈循环有利于PDAC进展和癌症恶病质。