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

项目摘要 胰腺癌（PC）患者的预后很差。几个团体的数据显示， 巨噬细胞对PC的显著浸润降低了化疗、放疗和免疫治疗的疗效 并与患者的不良临床结果相关。传统的假设是 这些肿瘤相关巨噬细胞来源于循环单核细胞。外地最近的变化 发育生物学的研究表明，这种假设并不完全正确，并提供了一个全新的观点， 巨噬细胞起源于许多组织。很明显，组织驻留巨噬细胞也可以产生于 在产前或围产期播种组织的胚胎前体。在我们最近发表的研究中， 建立了胚胎来源的巨噬细胞（eMAC）在PC进展中的关键作用。我们证明 这些结果表明：1）eMAC在PC进展过程中通过原位增殖呈指数增长，2）eMAC更有效 与单核细胞衍生的对应物相比，eMAC是PC进展的驱动因素，3）eMAC具有独特的组织 在体内显著增强PDAC纤维化的重塑表型。因此，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 疾病的不稳定性。我们的总体假设是表观遗传学上，胚胎学上， 来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因子 PC的发展。为了验证这个假设，我们将： 目标1。确定eMAC驱动纤维化和早期PDAC发病机制的机制。 目标2.确定eMAC促纤维化和促肿瘤活性的来源特异性表观遗传驱动因素。 目标3。确定eMAC对治疗反应性的影响。 影响：我们的经典假设是所有TAM都来源于单核细胞，但这可能不是 真的胚胎和/或组织驻留源性TAM可能影响PDAC进展， 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.