OVERCOMING STROMAL BARRIERS TO THERAPEUTICS IN PANCREAS CANCER

项目总结 胰腺导管腺癌(PDA)的致命性是无与伦比的。掌上电脑拥有最高的1- 年、5年和10年任何癌症的死亡率，预计将成为第二大 到2030年与癌症相关的死亡原因。侵袭性的PDA代表了细胞- 颠覆和改变正常的论断的内在和外在的过程和能力 组织组成、结构和生理学，以促进无节制的生长和定居。这是一项新的 组织实体在很大程度上是在突变的上皮细胞的要求下构建的。由此产生的 PDA新生器官包含少数肿瘤上皮细胞，在异质的非 上皮细胞；由蛋白质、蛋白多糖和糖胺多糖组成的复杂的间质炖锅 有自由流动的水和复杂的水；以及稀少的容器，否则就像一个 缺乏窗孔或内皮细胞连接的正常血管系统，但在 强烈的间质压力。我们对细胞的自主性进行了系统的探索 推动PDA发病和耐药的非细胞自主过程。我们已经开发出 基因工程动物模型忠实地概括了临床综合征，转移性 人类疾病的行为、组织病理学和分子特征作为两者的主要平台 发现疾病生物学的关键原理，并严格测试克服这些原理的策略。 通过这样的调查，我们发现了肿瘤内异常高浓度的 透明质酸(HA)是PDA间质压力异常升高的罪魁祸首， 进而导致本病特有的血管塌陷和低灌注率。《间质》 灌流屏障也是耐药的一个主要机制，限制了药物的渗透 系统交付的特工。此外，我们还确定了多种免疫机制 抑制，防止内源性效应T细胞反应的发展。总而言之， PDA间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地生长的避难所。最近，我们已经详细阐述了 克服这些治疗的生理和免疫障碍的关键方面的策略 一旦障碍被突破，就会暴露出可能出乎意料的脆弱程度。我们描述了一种 对基质再造这一总体战略的一系列持续调查，以此为基础 取得的重大进展--以及吸取的重要教训--希望从根本上 改变这一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 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.