Identifying Metabolic Vulnerabilities in Pancreatic Cancer

项目摘要/摘要 尽管最近在癌症治疗方面取得了进展，但胰腺癌(Pda)仍然是一种毁灭性的疾病。 随着发病率的增加。PDA对于目前的护理标准来说是非常难接受的，这在一定程度上是由于 重新连接新陈代谢，支持在严峻的肿瘤微环境中生长。因此，澄清 对于肿瘤生长至关重要的代谢途径对于理解PDA生物学的复杂性是必不可少的 以及寻找新的治疗机会。然而，有新的证据表明，体外新陈代谢 可能不能完全反映肿瘤的代谢需求。由于学习上的困难 用常规的体内代谢技术，建立了一种功能性遗传CRISPR筛选方法 被用来确定PDA肿瘤的代谢负债并全面定义关键代谢 原发肿瘤生长和转移的途径。 在提案的F99阶段，我分析了CRISPR筛查数据，以创建PDA代谢图 活体内的依赖性。我现在将使用这张PDA代谢依赖图来确定关键途径 在小鼠原位模型中支持肿瘤生长并评估这些通路作为潜在治疗靶点 胰腺癌。我还将确定支持生长的新陈代谢途径的机制 体外实验不需要体内实验。CRISPR筛选的初步分析表明，血红素的生物合成是 体内需要，但不是PDA细胞体外生长所必需的。我设计了一系列实验来 确定血红素生物合成如何支持肿瘤的生长，以及这种依赖如何在体外被掩盖 培养条件。 在这个提案的K00阶段，我将把重点从新陈代谢原发肿瘤转移到转移和 免疫系统。PDA是高度转移性的，转移是大多数癌症死亡的主要原因 病人。了解原发癌和转移癌之间的代谢差异将提供 洞察如何治疗转移性肿瘤以及如何靶向癌细胞代谢以增强免疫力 监测循环中的肿瘤细胞。 这项拟议的工作将是第一次对支持PDA在体内生长的途径进行全面分析 并将帮助确定治疗干预的候选对象。这些实验还将确定 原发肿瘤与转移性肿瘤的代谢差异及其与肿瘤细胞的相互作用 宿主的免疫系统。这些数据将告知哪些代谢途径会导致免疫逃避，以及是否有靶向 这些途径在治疗上将减少原发肿瘤的生长和转移肿瘤的负担。

Project Summary/Abstract Despite recent advances in cancer treatment, pancreatic cancer (PDA) remains a devastating disease with increasing incidence. PDA is highly refractory to the current standards of care which is due, in part, to a rewired metabolism that supports growth in an austere tumor microenvironment. Therefore, elucidating the metabolic pathways critical for tumor growth is imperative to understanding the complexities of PDA biology as well as identifying novel therapeutic opportunities. There is emerging evidence, however, that in vitro metabolism may not be entirely reflective of the metabolic requirements of a tumor. Due to the difficulties of studying metabolism in vivo with conventional techniques, a functional genetic CRISPR screening approach was employed to determine the metabolic liabilities of PDA tumors and comprehensively define critical metabolic pathways for primary tumor growth and metastasis. In the F99 phase of the proposal, I analyzed CRISPR screening data to create a map of PDA metabolic dependencies in vivo. I will now use this map of PDA metabolic dependencies to determine critical pathways to support tumor growth and evaluate these pathways as potential therapeutic targets in orthotopic mouse models of pancreatic cancer. I will also determine the mechanism by which a metabolic pathway that supports growth in vivo is not required in vitro. Preliminary analysis of the CRISPR screen suggest that heme biosynthesis is required in vivo but is not essential to growth of PDA cells in vitro. I have designed a series of experiments to determine how heme biosynthesis supports growth in tumors and how this dependency is masked by in vitro culture conditions. In the K00 phase of this proposal, I will shift focus from the metabolism primary tumor to metastasis and the immune system. PDA is highly metastatic and metastasis is the primary cause of mortality for most cancer patients. Understanding the differences between the metabolism of primary and metastatic cancer will offer insight into how to treat metastasized tumors and how to target cancer cell metabolism to increase immune surveillance of circulating tumor cells. The proposed work will be the first comprehensive analysis of pathways that support PDA growth in vivo and will help identify candidates for therapeutic intervention. These experiments will also determine the metabolic differences between primary and metastatic tumors and how cancer cell metabolism interacts with the host’s immune system. These data will inform what metabolic pathways lead to immune evasion and if targeting these pathways therapeutically will lead to a reduced primary tumor growth and metastatic tumor burden.