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

点击翻译按钮获取中文摘要

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.