The Impact of Macrophage Origin on the Pathogenesis and Treatment Resistance of Pancreatic Cancer

项目总结 胰腺癌(PC)患者预后较差。来自几个组织的数据表明， 巨噬细胞对PC的大量渗透降低了化疗、放射和免疫治疗的疗效 在动物模型中，并与患者不良的临床结果相关。经典的假设是 这些肿瘤相关巨噬细胞来源于循环中的单核细胞。该领域的最新变化 认为这种假设并不完全正确，并提供了一种全新的观点 巨噬细胞起源于许多组织。显然，驻留在组织中的巨噬细胞也可以从 胚胎前体，在产前或围产期为组织播种。在我们最近发表的研究中，我们 确定了胚胎来源的巨噬细胞(Emacs)在PC进展中的关键作用。我们演示了 这表明：1)Emacs在PC进展过程中通过原位增殖呈指数级扩张，2)Emacs更有效 PC进展的驱动因素比单核细胞来源的同类细胞更多，3)Emacs有明显的组织 显著增强体内PDAC纤维化的重塑表型。因此，对这一问题的进一步研究 PC中不同来源的巨噬细胞亚群之间的相互作用可能有助于理解 这种疾病的顽固性。我们的总体假设是表观遗传学上的平衡，胚胎上的 起源于胰腺的巨噬细胞是胰腺纤维化和早期疾病的关键调节细胞 个人电脑的进步。为了检验这一假设，我们将： 目的1.明确Emacs促纤维化和PDAC早期发病的机制。 目的2.确定eMac促纤维化和促肿瘤活性的来源特异性表观遗传学驱动因素。 目的3.确定Emacs对治疗反应性的影响。 影响：我们的经典假设是所有的TAM都来自单核细胞，但这可能不是 是真的。胚胎和/或组织来源的TAM可能会影响PDAC的进展和 对治疗的反应对基础科学和临床护理都有重要意义。

PROJECT SUMMARY The prognosis for pancreatic cancer (PC) patients is poor. Data from several groups has shown that significant infiltration of PC by macrophages decreases the efficacy of chemo-, radiation- and immunotherapy in an animal models and correlates with poor clinical outcomes in patients. The classical assumption has been that these tumor-associated macrophages are derived from circulating monocytes. Recent changes in the field of developmental biology suggest this assumption is not entirely correct and offer a radically new view of macrophage origins in many tissues. It is apparent that tissue-resident macrophages can also arise from embryonic precursors that seed tissues in pre- or perinatal periods. In our recently published study we established a key role for embryonically-derived macrophages (eMACs) in PC progression. We demonstrated that: 1) eMACs expand exponentially during PC progression by in situ proliferation, 2) eMACs are more potent drivers of PC progression than their monocyte-derived counterparts, and 3) eMACs have a distinct tissue remodeling phenotype that significantly enhances PDAC fibrosis in vivo. Thus, a further study of the interactions between various origin-based subsets of macrophages in PC may lead to an understanding of the recalcitrant nature of the disease. Our overall hypothesis is that epigenetically poised, embryonically derived pancreas-resident macrophages are critical regulators of pancreatic fibrosis and early disease progression in PC. To test this hypothesis we will: Aim 1. Determine the mechanisms by which eMACs drive fibrosis and early PDAC pathogenesis. Aim 2. Determine the origin-specific epigenetic drivers of eMAC pro-fibrotic and pro-tumor activity. Aim 3. Determine the impact of eMACs on therapeutic responsiveness. Impact: Our classical assumption was that all TAMs are derived from monocytes, however this may not be true. The fact that embryonic- and/or tissue resident-derived TAMs might impact PDAC progression and response to therapy has significant implications for both basic science and clinical care.