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 组织实体是在突变的上皮细胞的要求下构建的。由此产生的PDA neo- 器官在异质的非上皮细胞海洋中包含少数肿瘤上皮细胞； 蛋白质、蛋白多糖和糖胺聚糖的复合间质炖煮，以及两者的自由 流动和复杂的水；以及稀少的血管，否则类似于正常的血管系统 缺乏窗孔或内皮细胞间连接，但在强烈的间质液体下塌陷 压力。我们对细胞自治和非细胞进行了系统的探索 推动PDA发病和耐药的自主过程。我们是从基因上进化出来的 经过改造的动物模型，忠实地概括了临床综合征、转移行为、 人类疾病的组织病理学和分子特征作为揭示两者的主要平台 疾病生物学的关键原理，并严格测试克服这些原理的策略。通过这样的方式 调查发现，肿瘤内异常高浓度的透明质酸(HA)是 PDA间质液体压力(IFP)异常升高的主要罪魁祸首，进而导致 血管萎缩这种疾病的特点是血管收缩和低灌流。间质屏障对灌流的影响 也是限制肿瘤系统性侵袭的主要耐药机制 派来的特工。我们还发现了多种免疫抑制机制， 防止内源性效应T细胞反应的发展。总的来说，这些独一无二的 PDA间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 胰腺癌细胞的生长畅通无阻。最近，我们制定了战略，以 克服这些治疗的物理和免疫障碍的关键方面，可能揭示了 一旦障碍被突破，就会出现意想不到的脆弱性。我们描述了一系列持续的 对这一基质再造战略的调查，以扩大已取得的重大进展 希望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.