Fibroblast orchestration of the immune response in pancreatic cancer

胰腺癌是一种致命的恶性肿瘤，迫切需要新的治疗方法。胰腺癌是 以广泛堆积的纤维炎性间质为特征，含有丰富的成纤维细胞。长 成纤维细胞被认为是一个统一的细胞群体，已经成为一种异质的、具有重要功能的细胞 肿瘤的组成部分。然而，关于成纤维细胞在胰腺癌中的研究文献是有争议的。 既支持促肿瘤作用，也支持抗肿瘤作用。我们的初步数据显示，致癌的KRAS是一个标志 胰腺癌的突变，在肿瘤细胞中表达，外源性地重新编程转录程序 成纤维细胞。此外，上皮性致癌kras的持续表达需要维持a的表达。 成纤维细胞中的炎性细胞因子群。与老鼠肿瘤不同，人类胰腺癌的发病率很高。 在肿瘤细胞的遗传改变和组织学特征方面的异质性。成纤维细胞是如何 在不同类型的人类胰腺癌的背景下重新编程及其对 致癌机制尚不清楚。最后，大多数关于胰腺癌的深入研究都是基于大部分白人患者 虽然这种疾病在所有种族群体中同样普遍，但在所有人群中都是如此。密歇根大学/亨利·福特 卫生系统团队共同接触到大量不同的患者群体(30%的HFHS 患者是非裔美国人)，以及对成纤维细胞进行表征和功能评估的技能 胰腺癌。我们将绘制不同患者群体中肿瘤间成纤维细胞的异质性图谱。我们会 评估成纤维细胞的异质性是否与不同的肿瘤细胞亚型(归类为经典肿瘤细胞)相关 和间充质细胞)。我们将进一步利用我们的 小组针对不同癌变阶段的成纤维细胞重编程。总体而言，我们的工作将揭示 胰腺CAF的调节和功能及其靶向治疗开辟新途径 这群人。

Pancreatic cancer is a deadly malignancy, direly in need of new therapeutic approaches. Pancreatic cancer is characterized by extensive accumulation of a fibroinflammatory stroma, containing abundant fibroblasts. Long believed to be a uniform cell population, fibroblasts have emerged as a heterogeneous and functionally important component of the tumor. Yet, the literature on fibroblasts in pancreatic cancer is controversial, with studies supporting both a pro- and an anti-tumor role. Our preliminary data show that oncogenic KRAS, a hallmark mutation of pancreatic cancer, expressed in tumor cells extrinsically reprograms the transcriptional program of fibroblasts. Further, continuous expression of epithelial oncogenic Kras is required to maintain expression of a panel of inflammatory cytokines in fibroblasts. Unlike mouse tumors, human pancreatic cancer is highly heterogeneous in terms of genetic alterations and histological characteristics of cancer cells. How fibroblasts are reprogrammed in the context of different types of human pancreatic cancer and how they contribute to carcinogenesis is unclear. Lastly, most in depth studies on pancreatic cancer are based on largely White patient populations, while the disease is equally prevalent in all race groups. The University of Michigan/Henry Ford Health System team together has access to a large patient volume, diverse patient populations (with 30% HFHS patients being African American), and the skillset to characterize and functionally assess fibroblasts on pancreatic cancer. We will map fibroblast heterogeneity across tumors in a diverse patient population. We will evaluate whether fibroblast heterogeneity correlates with different subtypes of tumor cells (classified as classical and mesenchymal). We will further take advantage of the genetically engineered mouse models available in our group to target fibroblast reprogramming at different stages of carcinogenesis. Overall, our work will shed light on the regulation and function of pancreatic CAFs and open the way for new therapeutic approaches targeting this population.