Impact of RB activation on the pancreatic cancer epigenome and tumor microenvironment

胰腺导管腺癌(PDAC)是一种治疗顽固性疾病，其5年生存率为 大约10%。多项失败的临床试验加强了使用新的治疗方法的必要性 合理开发针对PDAC肿瘤和肿瘤关键基因特征的治疗方法 微环境。从根本上说，PDAC是KRAS驱动的肿瘤；然而，靶向KRAS的方法 从遗传学或药理学的角度来看，人们已经认识到肿瘤可以进化出使细胞继续生长的机制。 在有这种干预的情况下进行分裂。使用无偏见的分析和患者得出的组合 我们发现大多数肿瘤的进化机制是解除对视网膜母细胞瘤肿瘤抑制因子的调控。 (RB)限制靶向RAS或效应器途径的有效性的途径(例如，MEK抑制)。 因此，Rb的激活足以限制PDAC模型的增殖和肿瘤生长。 除了对增殖的影响外，我们还发现Rb的激活足以协调 影响PDAC经典亚型与基础亚型相关基因和免疫基因的基因表达 表达计划(例如抗原提呈和干扰素反应)。与细胞周期反应不同，这些反应 基因表达的变化更具异质性，其潜在机制和关键调控 人们对这些元素仍然知之甚少。在目标1中，我们将描述Rb的调节和基因的机制 PDAC模型中的表达调控。虽然Rb状态显然对肿瘤细胞分裂有影响，但一个重要的 Rb途径激活的因素与肿瘤微环境有关。初稿和出版 数据表明，Rb的激活对肿瘤间质和免疫环境有广泛的影响。其中大部分都是 研究采用了对肿瘤和宿主都有影响的系统性策略。在初步数据中，我们 已经发现Rb在肿瘤内的选择性激活足以改变成纤维细胞和 免疫细胞亚型与肿瘤，尽管不在系统治疗的同一水平。在这里，我们将 询问肿瘤和微环境之间的交集以及它们如何影响肿瘤--静态 并可通过免疫治疗方法加以利用。总之，Aim 2将定义RB的影响- 免疫活性模型结合临床对肿瘤微环境的激活作用 标本。

Pancreatic ductal adenocarcinoma (PDAC) represents a therapy recalcitrant disease with 5-year survival rate of approximately 10%. Multiple failed clinical trials reinforce the need for new approaches to treatment that employ rationally developed therapies targeting key genetic features of PDAC tumors as well as the tumor microenvironment. Fundamentally PDAC is a KRAS-driven tumor; however, approaches to target KRAS either genetically or pharmaceutically have led to the realization that tumors can evolve mechanisms to continue cell division in the presence of such interventions. Using a combination of unbiased analyses and patient derived models we find that most tumors have evolved mechanisms to deregulate the retinoblastoma tumors suppressor (RB) pathway that limits the effectiveness of targeting RAS or effector pathways (e.g. MEK inhibition). Consequently, the activation of RB is sufficient to limit the proliferation and tumorigenic growth of PDAC models. In addition to effects on the proliferation, we have found that RB activation is sufficient to coordinate changes in gene expression that impact on genes related to classical vs. basal subtypes of PDAC and immunological gene expression programs (e.g. antigen presentation and interferon response). Unlike cell cycle responses, these changes in gene expression are more heterogeneous and the underlying mechanisms and key regulatory elements remain poorly understood. In Aim 1 we will delineate the RB regulation and mechanisms of gene expression regulation in PDAC models. While RB status clearly has effects on tumor cell division, an important element of RB-pathway activation are effects related to the tumor microenvironment. Preliminary and published data indicate that RB activation has broad effects on the tumor stroma and immunological milieu. Much of these studies have employed systemic strategies that impact on both the tumor and the host. In preliminary data, we have found that activation of RB selectively within the tumor is sufficient to change the fibroblastic and immunological cell subtypes with the tumor, albeit not at the same level of systemic treatments. Here we will interrogate the intersection between the tumor and the microenvironment and how these impact tumor-static response and can be exploited by immunotherapy approaches. Together, Aim 2 will define the impact of RB- activation on the tumor microenvironment using a combination of immune competent models and clinical specimens.