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.

摘要 肥胖是一个世界性的公共卫生问题，其发病率正以惊人的速度增长。肥胖症协会 具有包括胰腺导管腺癌（PDAC）在内的许多恶性肿瘤的增加的风险和更差的预后。 然而，对潜在的机制知之甚少。肥胖会在局部引起促炎状态， 在脂肪组织中和全身性地在内脏器官如胰腺中。PDAC是一种高度促纤维增生/纤维化的 血管紧张素II受体1（AT 1）信号传导激活胰腺星状细胞（PSC）的肿瘤， 实体应力（肿瘤实体成分施加的机械力）。我们最近发现肥胖- 诱导的炎症破坏促结缔组织增生性肿瘤微环境（TME），并损害灌注， PDAC中的氧合和化疗（Cancer Discovery 2016）。我们的初步数据表明肥胖增加 肿瘤僵硬和固体应力，压缩血管并阻碍细胞毒性药物的输送和功效 疗法促结缔组织增生反应还促进癌细胞中的促存活信号传导。我们还发现了串话 肥胖小鼠PDAC中纤维化（AT 1）和炎症（白细胞介素-1 β（IL-1β））信号通路之间的关系。这些 异常也促进免疫抑制。在这些令人兴奋的发现的基础上，我们将进一步剖析 和机械机制，并开发新的策略，以克服这些肥胖引起的生物力学障碍 PDAC的成功治疗。我们假设靶向AT 1和/或IL-1β将减轻肥胖诱导的 结缔组织增生和重新编程免疫TME。为此，我们将研究自发和原位PDAC 在原发性和肝转移情况下具有饮食诱导的肥胖（DIO）的小鼠。这些PDAC模型具有 成功再现了临床疾病。我们将使用一种新的方法来表征DIO中PDAC的机械性能。 开发的方法与生化和细胞微环境的评估。我们将评估 新型TME激活的AT 1阻断剂（TMA-ARB）的作用，其允许向肿瘤递送高剂量ARB， 我们还将研究FDA批准的IL-1受体拮抗剂（IL-1 Ra，阿那白滞素）， 肥胖改变的PDAC生物力学，以及肥胖中的炎性细胞因子和细胞（目的1）。我们将评估是否 TMA-ARBs/ IL-1 Ra可在肥胖PDAC中重编程免疫TME（目的2）。最后，我们将确定如何 使用体外工程微环境提高固体应力和刚度改变肿瘤细胞和宿主基质细胞 其结果在体内进行测试（目标3）。我们预期TMA-ARB和/或IL-1 Ra将减轻结缔组织增生 肥胖小鼠PDAC中的炎症，重新编程ECM和免疫TME， 化疗和免疫检查点阻断剂免疫疗法。如果成功，这些研究将导致 为肥胖PDAC患者开发新的治疗策略。这些新的治疗方法可以迅速转化为 根据我们与优秀临床医生合作的成功临床翻译记录，