Mechanisms of myeloid cell driven pancreatic plasticity and carcinogenesis

摘要 胰腺癌几乎总是与一种致癌的、过度活化的形式有关 KRAS基因。致癌性KRAS突变存在于大多数人胰腺上皮内 肿瘤（PanIN）。Kras癌基因在基因工程胰腺上皮中的表达 小鼠模型（GEMM）模拟人类致癌作用，并提供了一个系统，研究早期阶段的癌症， 在一个完整的微环境中的疾病。胰腺癌的发生需要 上皮细胞去分化为导管样、祖细胞样细胞，其对致癌性肿瘤易感， 转型在此过程中，以及在PanIN和癌症的整个进展过程中， 病变周围的微环境被肿瘤细胞重新编程，反过来， 致癌作用在PanIN和胰腺癌的最丰富的成分中， 微环境是骨髓细胞，包括巨噬细胞，粒细胞和几个群体的 未成熟的骨髓细胞我们以前已经证明，骨髓细胞是需要的发病， 它们促进腺泡细胞去分化和早期病变的持续增殖。 此外，在晚期疾病中，骨髓细胞抑制T细胞介导的抗肿瘤免疫应答。 然而，骨髓细胞可以有相反的作用，促进组织修复和重塑，而不是 致癌作用这个提议的目的是研究肿瘤细胞和骨髓细胞之间的串扰， 细胞在胰腺癌发生、发展和维持过程中的作用。使用组合 人类患者样品和基因工程小鼠模型的研究，以及体内、体外和 通过硅方法，我们建议绘制健康人骨髓细胞群和功能状态， 胰腺、PanIN和人和小鼠胰腺癌（目的1）;定义髓样细胞的功能 细胞在不同阶段的致癌作用（目标2）;并重新编程骨髓细胞，以预防/治疗胰腺癌 癌症（目标3）。这些目标将共同促进我们对关键细胞相互作用的理解， 调节胰腺癌的发生，并确定和测试新的联合治疗方法， 疾病

Abstract Pancreatic cancer is almost invariably associated with the presence of an oncogenic, hyper-activated form of the KRAS gene. Oncogenic KRAS mutations are present in most human Pancreatic Intraepithelial Neoplasia (PanIN). Expression of oncogenic Kras in the pancreas epithelium of genetically engineered mouse models (GEMM) mimics human carcinogenesis, and provides a system to study early stages of the disease within the context of an intact microenvironment. The onset of pancreatic carcinogenesis requires dedifferentiation of epithelial cells to a duct-like, progenitor-like cell that is susceptible to oncogenic transformation. During this process, and throughout the progression of PanIN and cancer, the microenvironment surrounding the lesions is reprogrammed by tumor cells and, in turn, promotes carcinogenesis. Among the most abundant components of the PanIN and pancreatic cancer microenvironment are myeloid cells, including macrophages, granulocytes and several populations of immature myeloid cells. We have previously shown that myeloid cells are required for the onset of carcinogenesis, as they promote acinar cell dedifferentiation and sustained proliferation of early lesions. Further, in advanced disease, myeloid cells inhibit T cell mediated anti-tumor immune responses. However, myeloid cells can have the opposite effect, promoting tissue repair and remodeling rather than carcinogenesis. The goal of this proposal is to investigate the crosstalk between tumor cells and myeloid cells during the onset, progression and maintenance of pancreatic carcinogenesis. Using a combination of human patient samples and genetically engineered mouse models, as well as in vivo, in vitro and in silico approaches, we propose to map myeloid cell populations and functional status in the healthy pancreas, in PanIN, and in pancreatic cancer in human and mouse (Aim 1); define the function of myeloid cells at different stages of carcinogenesis (Aim 2); and reprogram myeloid cells to prevent/treat pancreatic cancer (Aim 3). Together these aims will advance our understanding of key cellular interactions that regulate pancreas carcinogenesis, and identify and test new combination therapy approaches for this disease.