Overcoming stromal barriers to therapeutics in pancreas cancer

项目摘要 胰腺导管腺癌（PDA）的致死率是无与伦比的。PDA拥有最高的1- 任何癌症的1年、5年和10年死亡率，预计将成为第二大 到2030年癌症相关死亡的原因。一个侵入性的PDA代表了细胞的协调进化- 内在和外在的过程和能力，颠覆和重新利用正常的格言， 组织组成、结构和生理学来促进无节制的生长和定殖。这个新 在突变的上皮细胞的命令下构建组织实体。由此产生的PDA neo- 器官在非上皮细胞的异质海洋中含有少数肿瘤上皮细胞; 蛋白质、蛋白聚糖和糖胺聚糖的复杂间质混合物， 移动的和复杂的水;以及缺乏血管，否则类似于正常的脉管系统， 缺乏窗孔或上皮间连接，但在强烈的间质液下塌陷 压力我们对细胞自主性和非细胞性进行了系统的探索 驱动PDA发病和耐药性的自主过程。我们从基因上 工程化动物模型忠实地再现了临床综合征，转移行为， 人类疾病的组织病理学和分子特征作为主要平台， 疾病生物学的关键原则，并严格测试克服它们的策略。通过这样 研究表明，异常高浓度的肿瘤内透明质酸（HA）是 动脉导管未闭（PDA）组织间液压力（IFP）异常升高的主要原因， 这种疾病的血管塌陷和低灌注特征。灌注间质屏障 也是限制肿瘤系统性渗透的主要耐药机制 交付的代理商。我们还发现了多种免疫抑制机制， 防止内源性效应T细胞应答的发展。这些独特的 PDA中基质生物学的各个方面共同创造了一个药物和免疫特权的避难所， 阻止胰腺癌细胞的生长。最近，我们制定了战略， 克服这些物理和免疫障碍的关键方面，以治疗揭示了一个也许 一旦障碍被突破，就会出现意想不到的脆弱程度。我们描述了一系列持续的 对这种基质再造战略的调查，以扩大所取得的重大进展， 希望能从根本上改变这种可怕疾病的治疗方法和预后。

PROJECT SUMMARY Pancreatic ductal adenocarcinomas (PDA) are unrivaled in their lethality. PDAs have the highest 1- year, 5-year, and 10-year mortalities of any cancer and are expected to become the second-leading cause of cancer-related death by 2030. An invasive PDA represents the coordinated evolution of cell- intrinsic and extrinsic processes and capabilities that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster unbridled growth and colonization. This new organizational entity is constructed at the behest of the mutated epithelial cell. The resulting PDA neo- organ contains a minority of tumor epithelial cells amidst a heterogeneous sea of non-epithelial cells; a complex interstitial stew of proteins, proteoglycans and glycosaminoglycans, together with both freely mobile and complexed water; and a paucity of vessels that otherwise resemble a normal vasculature in lacking fenestrae or interendothelial junctions, but that are collapsed under intense interstitial fluid pressures. We have undertaken a systematic exploration of the cell autonomous and non-cell autonomous processes that drive PDA pathogenesis and resistance. We have developed genetically engineered animal models that faithfully recapitulate the clinical syndrome, metastatic behavior, histopathology and molecular features of the human disease as primary platforms to both uncover critical principles of disease biology and to rigorously test strategies to overcome them. Through such investigations we have identified unusually high concentrations of intratumoral hyaluronan (HA) as the primary culprit in the extraordinarily elevated interstitial fluid pressures (IFP) in PDA that, in turn, cause the vascular collapse and hypoperfusion characteristic of this disease. The stromal barrier to perfusion also serves as a primary mechanism of drug resistance in limiting the tumor penetration of systemically delivered agents. We have additionally identified multiple mechanisms of immune suppression that prevent the development of an endogenous effector T cell response. Collectively, these unique aspects of stromal biology in PDA conspire to create a drug- and immune-privileged sanctuary for unimpeded growth of the pancreas cancer cell. Very recently, we have elaborated strategies to overcome critical aspects of these physical and immunological barriers to therapy revealing a perhaps unexpected degree of vulnerability once the barriers are breached. We describe a series of continuing investigations into this strategy of stromal re-engineering to expand upon the significant inroads made in the hopes of radically transforming the approach and prognosis for this formidable disease.