THE EVOLUTION OF PGD ADDICTION IN HUMAN PANCREATIC CANCER

项目摘要(摘要) 远处转移是大多数癌症死亡的原因。对于胰腺癌来说，情况尤其如此。这些 患者会出现数十万个突然出现并迅速进展的转移瘤，以填补 肝脏和肺。这种疾病的这一阶段是迅速致命的，人们对它知之甚少，而且对它的研究也严重不足。 长期目标：确定是什么驱动和/或加速了胰腺癌的转移阶段 并利用这些知识来设计新的有效的治疗策略。 研究设计：该提案旨在深入研究一种名为PGD的代谢酶是如何 导致胰腺癌转移。我们最近发现糖(葡萄糖)能激活PGD，而且曾经 PGD被激活，它强烈刺激转移性肿瘤的生长。了解癌细胞如何利用葡萄糖 激活PGD以及PGD如何促进肿瘤生长是重要的：它可能导致第一个有效的 针对最常见和最致命的疾病进展阶段的治疗策略。 研究方法：实验将使用一组强大的转移性胰腺癌细胞和组织 是从死于这种疾病的个别患者身上收集的。独特的三维实验 平台将使我们能够调查这些癌症是如何在患者体内形成转移肿瘤的。 实验将特别关注转移细胞如何将葡萄糖处理成可激活的代谢物。 PGD酶，以及激活的PGD酶如何能够促进转移性肿瘤的生长。 目的1：确定葡萄糖是如何在远处转移瘤中促进高PGD催化活性的。 目标1将研究一系列不寻常的代谢反应如何将葡萄糖转化为代谢物 激活PGD。我们最近的工作是第一次在人类身上检测到这些反应。那是因为他们只是 在转移性癌细胞中运作。它们的功能是支持PGD驱动的转移。 目的2：明确前列腺素D在远处转移中被结构性激活的机制。 目标2将研究激活的PGD如何能够加速葡萄糖消耗和脂肪消耗的速度 转移性癌细胞中酸的生物合成。这不仅有力地促进了转移性肿瘤的生长，而且 也使PGD处于永久激活状态，在有葡萄糖存在的情况下无法关闭。 目的3：研究PGD如何重新编程表观基因组以激活转移的转录组。 目标3将研究PGD是如何控制“表观基因组”的，表观基因组指的是微小的化学修饰 在染色质内，调节DNA序列中编码的基因(“转录组”)的表达。 PGD通过加速葡萄糖消耗对胰腺癌表观基因组重新编程。转移的细胞 将多余的葡萄糖分解成较小的表观遗传化学物质。然后这些化学物质被用来增加 促进转移性肿瘤生长和赋予治疗耐药性的众多基因的表达。

PROJECT SUMMARY (ABSTRACT) Distant metastasis is the cause of most cancer deaths. This is particularly true for pancreatic cancer. These patients develop hundreds to thousands of metastases that appear suddenly and progress rapidly to fill the liver and lungs. This stage of the disease is rapidly lethal, poorly understood, and grossly understudied. Long-term Objectives: Characterize what drives and/or accelerates the metastatic stage of pancreatic cancer in patients, and use this knowledge to design new and effective treatment strategies. Research Design: This proposal is designed to deeply characterize how a metabolic enzyme named PGD drives pancreatic cancer metastasis. We recently discovered that sugar (glucose) activates PGD, and once PGD is activated it strongly stimulates metastatic tumor growth. Understanding how cancer cells use glucose to activate PGD and how PGD then promotes tumor growth is important: it could lead to the first effective treatment strategies against the most common and most lethal stage of disease progression. Research Methods: Experiments will use a powerful set of metastatic pancreatic cancer cells and tissues that were collected from individual patients who died of the disease. Unique three-dimensional experimental platforms will allow us to investigate how these cancers learned to form metastatic tumors in the patients. Experiments will specifically focus on how the metastatic cells process glucose into metabolites that activate the PGD enzyme, and how the activated PGD enzyme is then able to enhance metastatic tumor growth. Aim 1: Determine how glucose fuels high PGD catalytic activity in distant metastases. Aim 1 will investigate how an unusual series of metabolic reactions convert glucose into metabolites that activate PGD. Our recent work was the first to detect these reactions in humans. That is because they are only operational in the metastatic cancer cells. Their function is to support PGD-driven metastasis. Aim 2: Define the mechanism whereby PGD is constitutively activated in distant metastases. Aim 2 will investigate how activated PGD is able to accelerate the rates of both glucose consumption and fatty acid biosynthesis in the metastatic cancer cells. This not only strongly promotes metastatic tumor growth, but also maintains PGD in a perpetually activated state that cannot be switched off in the presence of glucose. Aim 3: Investigate how PGD reprograms the epigenome to activate the metastatic transcriptome. Aim 3 will investigate how PGD is able to control the “epigenome”, which refers to small chemical modifications within chromatin that regulate expression of the genes encoded in the DNA sequence (the “transcriptome”). PGD reprograms the pancreatic cancer epigenome by accelerating glucose consumption. The metastatic cells break the extra glucose down into the smaller epigenetic chemicals. The chemicals are then used to increase expression of numerous genes that enhance metastatic tumor growth and bestow treatment resistance.