Autocrine and paracrine mechanisms of HA-driven metastasis in pancreas cancer

HA驱动的胰腺癌转移的自分泌和旁分泌机制

• 批准号: 9761189
• 负责人: Heather Jeanne Wright
• 金额: $ 2.67万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2019-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761189
• 关键词: Anoikis; Autocrine Communication; Automobile Driving; Behavior; Binding; Biological Models; Biology; Blood Circulation; Breast; CD44 Antigens; CD44 gene; Cancer Model; Carcinoma; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell surface; Characteristics; Clinic; Clinical; Colon; Dependence; Desmoplastic; Disaccharides; Disease; Drug resistance; Enzymes; Epithelial; Epithelial Cells; Excision; Extracellular Matrix; Extracellular Space; Extravasation; Family; Fibroblasts; Gel; Genetic; Genetic Transcription; Genetically Engineered Mouse; Glucosamine; Glucuronic Acids; Glycosaminoglycans; Goals; HAS2 gene; HAS3 gene; HMMR gene; Histopathology; Human; Hyaluronan; Hyaluronidase; Integrins; Intercellular adhesion molecule 1; Investigation; Liquid substance; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of pancreas; Mechanics; Mediating; Mesenchymal; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Weight; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Paracrine Communication; Pathogenicity; Pathway interactions; Patients; Perfusion; Phase III Clinical Trials; Plasma; Play; Polymers; Primary Neoplasm; Process; Production; Quantitative Reverse Transcriptase PCR; Receptor Signaling; Resistance; Role; SPAM1 gene; Shelter facility; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Swelling; Symptoms; Validation; Water; angiogenesis; autocrine; base; cancer cell; chemotherapy; clinical practice; experimental study; human disease; hyaluronan synthase 1; hydrophilicity; improved; in vivo; insight; interstitial; intravenous administration; knock-down; migration; mortality; neoplastic cell; next generation sequencing; novel; overexpression; pancreatic cancer model; paracrine; pressure; receptor binding; receptor expression; receptor-mediated signaling; response; rho; tumor; tumor initiation; tumor progression

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) has the highest 1-, 5-, and 10- year mortality because more than 80% of patients present with locally advanced or metastatic disease, precluding an attempt at surgical resection. PDA is characterized by a robust desmoplastic reaction that promotes cancer cell dissemination through direct interactions with tumor epithelial cells (TECs) and surrounding stromal cells, including cancer- associcated fibroblasts (CAFs). This desmoplasia also makes PDA unusually resistant to systemic chemotherapies by acting as a physical barrier sheltering it from treatment. Our lab previously identified hyaluronan (HA) as a defining feature of this desmoplasia that generates remarkably elevated interstitial pressures capable of collapsing intratumoral vasculature. HA is a unique hydrophilic glycosaminoglycan composed of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine. It is synthesized by the HA synthase (Has) family of enzymes, Has1, Has2, and Has3, of which Has2 produces the highest molecular weight (MW) polymers. This is important because higher MW HA polymers bind greater amounts of water and expand more than lower MW species, resulting in greater swelling pressures. In PDA epithelial cells, we found that HA was almost exclusively produced by Has2. In addition to its mechanical contributions to the PDA microenvironment, HA also functions as a signaling molecule to promote cancer progression. HA forms a pericellular coat around tumor cells through interactions with HA-binding proteins at the cell surface, which assists in tumor cell extravasation and anoikis resistance during metastasis. HA also binds cell surface receptors, including CD44, RHAMM, and ICAM-1, to induce signaling in TECs and CAFs. HA signaling in TECs and CAFs promotes tumor initiation, progression, invasion, angiogenesis, metastasis, and drug resistance. Using a genetically engineered mouse model of pancreas cancer, KrasG12D/+;Trp53R172H/+;p48Cre/+ (KPC), that faithfully recapitulates the pathobiology of the human disease, we demonstrated that enzymatic degradation of intratumoral HA with pegylated hyaluronidase (PEGPH20) drastically reduced interstitial gel- fluid pressures and improved perfusion and response to chemotherapy. This combined enzymatic and chemotherapy strategy has progressed rapidly in the clinic and is now in a global Phase 3 trial. Recently, we developed models to conditionally delete Has2 heterozygously (KPHC) and homozygously (KPHHC) in the pancreatic epithelial cells of KPC mice. We have observed a striking reduction in metastatic burden and alteration of HA-receptor expression and signaling in KPHC and KPHHC PDA compared to KPC. I propose to investigate the autocrine and paracrine mechanism(s) of HA biology that drive PDA metastasis. The goals of these investigations are to understand the pathogenic implications of tumor epithelial cell-HA production in autocrine signaling, paracrine signaling to CAFs, and systemic circulation that combine to promote metastasis.

项目摘要 胰腺导管腺癌（PDA）的1年，5年和10年死亡率最高，因为 80％的患者患有局部晚期或转移性疾病，排除了尝试手术的尝试 切除。 PDA的特征是强大的脱糖反应，促进癌细胞传播 通过与肿瘤上皮细胞（TEC）和周围基质细胞的直接相互作用，包括癌症 联合成纤维细胞（CAFS）。这种脱粒化也使PDA异常抵抗全身性 化学疗法通过充当物理屏障避免治疗。我们先前确定的实验室 透明质酸（HA）作为这种脱木质的定义特征，该特征产生了极高的间隙 能够崩溃的肿瘤内脉管系统的压力。 HA是一种独特的亲水性糖胺聚糖 由D-葡萄糖酸和N-乙酰-D-葡萄糖的重复二糖单位组成。它是合成的 由HA合酶（HAS）酶，HAS1，HAS2和HAS 3，其中HAS2产生最高 分子量（MW）聚合物。这很重要，因为较高的MW HA聚合物结合了更多 水和膨胀比较低的MW物种，导致肿胀压力更大。在PDA上皮细胞中， 我们发现HA几乎是由HAS2制作的。除了其机械贡献 PDA微环境，HA还起到促进癌症进展的信号分子的作用。 ha形成a 通过与细胞表面上的HA结合蛋白相互作用，周围的细胞周围毛皮细胞周围的细胞外涂 在转移过程中有助于肿瘤细胞的渗出和抗动脉抗性。 HA还结合细胞表面 包括CD44，RHAMM和ICAM-1在内的受体在TEC和CAF中诱导信号传导。 HA信号在 TEC和CAF促进肿瘤的启动，进展，侵袭，血管生成，转移和药物 反抗。使用胰腺癌的基因工程小鼠模型，KRASG12D/+; TRP53R172H/+; P48CRE/+ （KPC），忠实地概括了人类疾病的病理生物学，我们证明了酶促的 肿瘤内HA降解透明质的透明质酸酶（PEGPH20）大大降低了间质凝胶 - 液体压力，改善了灌注和对化学疗法的反应。这种结合酶促和 化学疗法策略在临床上已经迅速发展，现在正在全球3期试验中。最近，我们 开发了有条件地删除HAS2杂合（KPHC）和纯合（KPHHC）的模型 KPC小鼠的胰腺上皮细胞。我们观察到转移负担的显着减轻和 与KPC相比，KPHC和KPHHC PDA中HA受体表达和信号传导的改变。我建议 研究驱动PDA转移的HA生物学的自分泌和旁分泌机制。这 这些研究的目标是了解肿瘤上皮细胞-HA的致病意义 自分泌信号传导，对CAF的旁分泌信号和全身循环中的产生 促进转移。