Reengineering obesity-induced abnormal microenvironment to improve PDAC treatment

重新设计肥胖引起的异常微环境以改善 PDAC 治疗

• 批准号: 9403496
• 负责人: Dai Fukumura
• 金额: $ 49.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403496
• 关键词: Adenocarcinoma Cell; Adipose tissue; Angiotensin II Receptor; Apoptosis; Atomic Force Microscopy; Biochemical; Biomechanics; Biomedical Engineering; Blood Vessels; Cells; Clinic; Clinical; Collaborations; Cytotoxic Chemotherapy; Data; Deposition; Desmoplastic; Development; Devices; Diet; Digestion; Disease; Dose; Effectiveness; Engineering; Enzymes; Extracellular Matrix; FDA approved; Fibrosis; Genetically Engineered Mouse; Goals; Hyaluronidase; Hypotension; Hypoxia; Immune; Immunosuppression; Immunotherapy; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Interleukin-1 Receptors; Interleukin-1 beta; Lead; Malignant Neoplasms; Maps; Measurement; Measures; Mechanics; Mediating; Metastatic Neoplasm to the Liver; Methods; Modeling; Modulus; Molecular; Morphology; Mus; Obese Mice; Obesity; Organ; Overweight; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Polymers; Process; Production; Property; Public Health; Publishing; Recruitment Activity; Research Project Grants; Resolution; Risk; Role; Signal Pathway; Signal Transduction; Solid; Spatial Distribution; Stress; Stromal Cells; System; Testing; Thinness; Tissues; Translating; Treatment outcome; Tumor Immunity; Ultrasonography; Visceral; anakinra; base; cancer cell; cell motility; chemokine; chemotherapy; clinical translation; cytokine; design; hypoperfusion; immune checkpoint; improved; in vivo; insight; mathematical model; mechanical force; mechanical properties; monolayer; mortality; mouse model; nanosized; neoplastic cell; neutrophil; novel; novel strategies; novel therapeutic intervention; outcome forecast; stellate cell; treatment strategy; tumor; tumor microenvironment

ABSTRACT Obesity is a worldwide public health problem, and its incidence is increasing at an alarming rate. Obesity associates with increased risk and worse prognosis of many malignancies including pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Obesity induces a pro-inflammatory state both locally in adipose tissue and systemically in visceral organs such as the pancreas. PDAC is a highly desmoplastic/fibrotic tumor in which angiotensin II receptor 1 (AT1) signaling activates pancreatic stellate cells (PSCs), contributing to solid stress (the mechanical force exerted by the solid components of the tumor). We have recently shown that obesity- induced inflammation worsens the desmoplastic tumor microenvironment (TME), and compromises perfusion, oxygenation and chemotherapy in PDACs (Cancer Discovery 2016). Our preliminary data suggest that obesity increases tumor stiffness and solid stress, which compress blood vessels and hinder the delivery and efficacy of cytotoxic therapy. The desmoplastic reaction also promotes pro-survival signaling in cancer cells. We also found crosstalk between fibrotic (AT1) and inflammatory (interleukin-1β (IL-1β)) signaling pathways in PDACs in obese mice. These abnormalities also promote immunosuppression. Building on these exciting findings, we will further dissect molecular and mechanical mechanisms and develop novel strategies to overcome these obesity-induced biomechanical barriers to successful therapy in PDACs. We hypothesize that targeting AT1 and/or IL-1β will alleviate obesity-induced desmoplasia and reprogram the immune TME. To this end, we will study spontaneous and orthotopic PDAC mice with diet-induced obesity (DIO) in both primary and liver metastasis settings. These PDAC models have successfully recapitulated clinical disease. We will characterize mechanical properties of PDACs in DIO using a newly developed approach together with the assessment of biochemical and cellular microenvironment. We will assess the effect of novel TME-activated AT1 blockers (TMA-ARBs), which allow delivery of high-dose ARBs to tumors while avoiding systemic hypotension We will also study the FDA approved IL-1 receptor antagonist (IL-1Ra, anakinra) on obesity-altered PDAC biomechanics, and on inflammatory cytokines and cells in obesity (Aim 1). We will evaluate if TMA-ARBs/ IL-1Ra can reprogram immune TME in PDACs with obesity (Aim 2). Finally, we will determine how elevated solid stress and stiffness alter tumor cells and host stromal cells using in vitro engineered microenvironments with the results being tested in vivo (Aim 3). We anticipate that TMA-ARBs and/or IL-1Ra will alleviate desmoplasia and inflammation in PDACs in obese mice, reprogram ECM and immune TME and facilitate both conventional chemotherapy and immune checkpoint blocker immunotherapy. If successful, these studies will lead to the development of novel treatment strategies for obese PDAC patients. These novel treatments can be rapidly translated into the clinic based on our track record of successful clinical translation in collaboration with outstanding clinicians.

抽象的 观察是一个全球公共卫生问题，并且以惊人的速度增加了发病率。 随着许多恶性肿瘤的风险增加，预后较差，包括胰腺尘土腺癌（PDAC）。 霍弗，基本机制在本地很差 在脂肪组织中以及诸如palcress之类的粘液中的系统中。 血管紧张素II受体1（AT1）信号传导激活胰腺星状细胞（PSC）的肿瘤。 固体应力（由肿瘤的固体成分施加的机械力）。 诱导的炎症恶化了去肿瘤的肿瘤微环境（TME），并损害了灌注， PDAC中的氧合和化学疗法（癌症发现2016）。 肿瘤刚度和固定应力，会压缩血液并阻碍细胞毒性的递送和功效 治疗。 在肥胖小鼠中，纤维化（AT1）和炎症（IL-1β）的炎症（IL-1β）。 异常也促进了令人兴奋的发现。 和机械机制和开发小说型新闻，以克服这些肥胖引起的生物力学屏障 在PDAC中成功治疗。 Desmoplasia和复印件的免疫TME。 这些PDAC模型的饮食诱导的小鼠肥胖（DIO）均具有。 成功概括的临床疾病。 开发的方法以及生化和细胞微卷积的评估。 新型的TME活性AT1阻滞剂（TMA-ARBS）的影响，允许将大剂量ARB递送到肿瘤中 避免系统性低血压，我们还将研究FDA认可的IL-1受体拮抗剂（IL-1RA，Anakinra） 肥胖的PDAC生物力学，以及肥胖症中的炎性细胞因子和细胞（AIM 1）。 TMA-ARBS/ IL-1RA可以在肥胖症中重新编程PDAC的免疫TME（AIM 2）。 升高应激僵硬改变了肿瘤细胞和宿主基质细胞，并使用体外ENGROENCORNTMENT 随着结果在体内进行测试（AIM 3）。 肥胖小鼠PDAC的炎症，重新编程ECM和免疫TME，并促进两者转化 化学疗法和免疫检查点阻滞剂免疫疗法。 肥胖PDAC患者的新型治疗策略可以迅速翻译 根据我们与杰出临床医生合作的成功清洁仪的记录，进入诊所。