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）具有最高的1年、5年和10年死亡率，因为超过20%的患者在治疗过程中死亡。 80%的患者存在局部晚期或转移性疾病，排除了手术尝试 切除术动脉导管未闭的特征是强烈的促结缔组织增生反应，促进癌细胞播散 通过与肿瘤上皮细胞（TEC）和周围基质细胞（包括癌症）的直接相互作用， 相关成纤维细胞（CAFs）。这种结缔组织增生也使PDA对全身性免疫抑制剂异常耐药。 通过充当物理屏障来保护它免受治疗。我们的实验室之前发现 透明质酸（HA）作为这种结缔组织增生的定义特征， 能够使肿瘤内脉管系统塌陷的压力。HA是一种独特的亲水性糖胺聚糖 由D-葡糖醛酸和N-乙酰基-D-葡糖胺的重复二糖单元组成。来合成 HA合成酶（Has）家族的酶，Has 1，Has 2和Has 3，其中Has 2产生最高的 分子量（MW）聚合物。这是重要的，因为较高MW的HA聚合物结合更大量的 水和膨胀比低分子量的物种，导致更大的溶胀压力。在PDA上皮细胞中， 我们发现HA几乎完全由Has 2产生。除了它的机械贡献， 在PDA微环境中，HA还作为信号分子促进癌症进展。房委会表格a 通过与细胞表面的HA结合蛋白相互作用， 在转移过程中帮助肿瘤细胞外渗和抗失巢凋亡。HA还结合细胞表面 受体，包括CD 44、RHAMM和ICAM-1，以诱导TEC和CAF中的信号传导。HA信号转导 TEC和CAF促进肿瘤的发生、进展、侵袭、血管生成、转移和药物治疗。 阻力使用胰腺癌基因工程小鼠模型，KrasG 12 D/+; Trp 53 R172 H/+; p48 Cre/+ (KPC)，忠实地概括了人类疾病的病理生物学，我们证明了酶促 用聚乙二醇化透明质酸酶（PEGPH 20）降解肿瘤内HA显著减少了间质凝胶- 液体压力和改善的灌注和对化疗的反应。这种结合了酶和 化疗策略在临床上进展迅速，目前正在进行全球3期试验。最近我们 开发的模型，有条件地删除Has 2异源（KPHC）和同源（KPHHC）， KPC小鼠的胰腺上皮细胞。我们已经观察到转移负荷显著降低， 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。的 这些研究的目的是了解肿瘤上皮细胞-HA的致病意义 产生自分泌信号，旁分泌信号到CAF，和体循环，联合收割机 以促进转移。