The role of HIF2alpha in colon carcinogenesis

摘要 结肠癌是美国癌症死亡的第二大原因。炎症是结肠癌发生和发展的重要组成部分。这种炎症性疾病和随后的肿瘤最著名的例子是结肠炎相关性结肠癌，慢性先前存在的炎症会增加癌症的风险。然而，即使是与先前存在的炎症性疾病无关的零星结肠癌，炎症也会影响生长和进展。我们的工作也仔细地证明了中性粒细胞的募集是HIF2α促进结肠癌生长的关键机制。我们最近发现，肠道微生物区系代谢产物是HIF2α表达和活性的重要调节因子。然而，目前尚不清楚微生物代谢产物在结肠癌HIF2α调节中的作用，低氧对中性粒细胞的调节是否具有细胞自主性作用，以及HIF2α在结肠癌中是否具有靶向性？这一研究领域尚未得到充分开发，有可能产生新的结肠癌治疗方法和靶向治疗。这项研究提案的总体目标是确定HIF2α通过协同代谢产物串扰促进结肠癌进展的机制基础。根据我们的初步数据，我们假设HIF2α在上皮细胞和中性粒细胞中的激活促进了免疫抑制环境，这在损伤和结肠癌进展后的肠道再生中至关重要。我们最近的工作发现，肠道微生物区系代谢产物作为HIF2α和AIM 1的本质调节因子，将阐明微生物代谢物轴是否是调节HIF2α在炎症和结肠癌中的主要机制。使用一只新的报告小鼠，我们发现中性粒细胞表达高水平的HIF2α，AIM 2将了解中性粒细胞中细胞自主的HIF2α调节是否对炎症和结肠癌中免疫抑制代谢物的产生至关重要。第一个靶向HIF2α抑制剂正在进行肾癌的临床试验，并证明了有希望的结果。在目标3中，我们将确定在结肠癌的临床前模型中，这种抑制剂是否单独或在免疫检查点阻滞剂的辅助环境下提供任何益处。实现这些目标将：(I)揭示HIF2α调控的机制；(Ii)定义改变中性粒细胞功能的新的代谢途径；(Iii)突出结肠癌的新途径、遗传脆弱性和药物靶点。

ABSTRACT Colon cancer is the second leading cause of cancer deaths in the United States. Inflammation is an essential component of colon cancer initiation and progression. Most notable examples for such inflammatory conditions and subsequent tumors include colitis-associated colon cancer, where chronic pre-existing inflammation increases the risk of cancer. However, even sporadic colon cancers that are not linked to pre-existing inflammatory disease, inflammation can impact growth and progression. Our works also has carefully demonstrated that the recruitment of neutrophils is a critical mechanism by which HIF2α promotes colon cancer growth. We recently have found that gut microbiota metabolites are essential regulators of HIF2α expression and activity. However, it is unclear the role of the microbial metabolites in HIF2α regulation in colon cancer, does hypoxia have a cell autonomous role in the regulation of neutrophils, and can HIF2α be targeted in colon cancer? This research area is underexplored and has the potential to generate novel therapies and therapeutic targeted in colon cancer. The overall objective of this research proposal is to define the mechanistic underpinnings by which HIF2α via cooperative metabolite crosstalk potentiate colon cancer progression. Based on our preliminary data, we hypothesize that HIF2α activation in epithelial cells and neutrophils promote an immunosuppressive environment is critical in intestinal regeneration following injury and colon cancer progression. Our recent work identified that gut microbiota metabolites as essentially regulators of HIF2α and Aim 1 will delineate if microbial metabolite axis is the major mechanism regulating HIF2α in inflammation and colon cancer. Using a novel reporter mouse, we identified that neutrophils express high levels of HIF2α and Aim 2 will understand if cell autonomous HIF2α regulation in neutrophils is critical for immunosuppressive metabolite production in inflammation and colon cancer. The first on-target HIF2α inhibitor is undergoing clinical trials for renal cancers and has demonstrated promising results. In Aim 3 we will determine if this inhibitor provides any benefit alone or in an adjuvant setting with immune checkpoint blockers in preclinical models of colon cancer. Accomplishing these Aims will (i) uncover mechanisms of HIF2α regulation (ii) define new metabolic pathways that alter neutrophil function, and (iii) highlight new pathways, genetic vulnerabilities and drug targets for colon cancer.