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，其发病率正在以惊人的速度增长。与肥胖有关的人 许多恶性肿瘤的风险增加和预后较差，包括胰腺导管腺癌(PDAC)。 然而，人们对其潜在的机制知之甚少。肥胖在两个局部都会导致促炎状态 在脂肪组织中，在内脏器官如胰腺中。PDAC是一种高度促结缔组织增生性/纤维化 血管紧张素II受体1(AT1)信号激活胰腺星状细胞(PSCs)的肿瘤，有助于 固体应力(肿瘤固体成分施加的机械力)。我们最近表明，肥胖-- 诱导的炎症会恶化促结缔组织增生性肿瘤微环境(TME)，并损害血流灌注， PDAC中的氧合作用和化疗(癌症发现2016)。我们的初步数据显示，肥胖增加 肿瘤僵硬和固体应力，压迫血管，阻碍细胞毒的传递和疗效 心理治疗。促结缔组织反应也促进了癌细胞中的促生存信号。我们还发现了相声 在肥胖小鼠的PDAC中，纤维化(AT1)和炎症(IL-1β，IL-1β)信号通路之间的关系。这些 异常也会促进免疫抑制。在这些令人兴奋的发现的基础上，我们将进一步剖析分子 和机械机制，并开发新的策略来克服这些肥胖引起的生物力学障碍 为PDAC的成功治疗干杯。我们假设靶向血管紧张素转换酶1和/或白介素1β将缓解肥胖诱导 结缔组织增生和重新编程免疫的TME。为此，我们将研究自发性和原位PDAC 饮食诱导肥胖(DIO)的小鼠在原发和肝转移环境中都是如此。这些PDAC型号具有 成功地概括了临床疾病。我们将使用一种新的方法来表征PDAC在DIO中的力学特性 开发了一种结合生化和细胞微环境评估的方法。我们将评估 新型TME激活的AT1阻滞剂(TMA-ARB)的作用，它允许将大剂量ARB输送到肿瘤，同时 避免全身性低血压我们还将研究FDA批准的IL-1受体拮抗剂(IL-1ra，Anakinra) 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(目标1)。我们将评估是否 TMA-ARBS/IL-1ra可以对肥胖的PDAC患者的免疫TME进行重新编程(目标2)。最后，我们将确定如何 利用体外工程微环境提高固体应力和硬度改变肿瘤细胞和宿主基质细胞 并对结果进行体内测试(目标3)。我们预计TMA-ARB和/或IL-1ra将缓解结缔组织发育不全 以及肥胖小鼠PDAC中的炎症，重新编程ECM和免疫TME，促进常规的 化疗和免疫检查点阻滞剂免疫治疗。如果成功，这些研究将导致 为肥胖的PDAC患者开发新的治疗策略。这些新颖的治疗方法可以迅速转化为 基于我们与优秀临床医生合作成功进行临床翻译的记录。