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 组织实体主要是在突变的上皮细胞的命令下构建的。所得 PDA新器官包含少数肿瘤上皮细胞， 上皮细胞;蛋白质、蛋白聚糖和糖胺聚糖的复杂间质混合物， 既有自由移动的，又有复杂的水;以及缺乏船只，否则就像一个 正常的血管系统缺乏窗孔或内皮间连接，但在 强烈的间隙压力。我们已经进行了系统的探索细胞自主和 非细胞自主过程驱动PDA发病机制和耐药性。我们已经开发 基因工程动物模型，忠实地概括了临床综合征，转移 行为，组织病理学和人类疾病的分子特征作为主要平台， 揭示疾病生物学的关键原则，并严格测试克服这些原则的策略。 通过这样的研究，我们已经确定了异常高浓度的肿瘤内 透明质酸（HA）是PDA中间质压异常升高的主要原因， 进而导致这种疾病的血管塌陷和灌注不足。该基质 灌注屏障也是限制药物渗透的主要耐药性机制。 全身递送的药剂。我们还发现了多种免疫机制， 抑制，其防止内源性效应T细胞应答发展。总的来说， PDA中基质生物学的这些独特方面共同创造了一种药物和免疫特权 胰腺癌细胞不受阻碍生长的庇护所。最近，我们详细阐述了 克服这些物理和免疫障碍的关键方面的治疗策略 揭示了一旦屏障被突破，可能会出现意想不到的脆弱程度。我们描述了一种 一系列持续的调查，这一总体战略的基质再造，以建立在 取得的重大进展-以及吸取的重要教训-希望从根本上 改变了治疗这种可怕疾病的方法和预后。

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 largely 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 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 pressures 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 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 overarching strategy of stromal re-engineering to build upon the significant inroads made – and the important lessons learned – in the hopes of radically transforming the approach and prognosis for this formidable disease.