Targeting Metabolic Liabilities in Cancer

针对癌症的代谢负担

• 批准号: 10079472
• 负责人: Richard Lewis Possemato
• 金额: $ 39.07万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079472
• 关键词: Affect; Anabolism; Animal Model; Antioxidants; Area; Automobile Driving; Bioenergetics; Biomass; Breast Cancer Model; Breast Cancer cell line; Breast cancer metastasis; Cell Death; Cell Survival; Cells; Cessation of life; Critical Pathways; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Replication Induction; DNA Replication Inhibition; DNA biosynthesis; DNA replication fork; DNA replication origin; Data; Defect; Dependence; Environment; Enzymes; Essential Genes; Future; Genes; Genetic Screening; Glucose; Glutathione; Goals; Grant; Human; In Vitro; Individual; Iron; Iron Overload; Lead; Lung; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Lung; Modeling; Molecular; Normal tissue morphology; Oncogene Activation; Oxidants; Oxidative Stress; Oxygen; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Process; Proteins; RNA Interference; Reaction; Role; Serine; Serous; Starvation; Stress; Sulfur; Work; Xenograft Model; Xenograft procedure; base; breast cancer genomics; cancer cell; cancer subtypes; cancer survival; cancer therapy; cell transformation; cofactor; driving force; experimental study; genome integrity; in vivo; inhibitor/antagonist; iron metabolism; malignant breast neoplasm; oxidative damage; repaired; response; triple-negative invasive breast carcinoma; tumor; tumor metabolism; tumor microenvironment; tumor xenograft; tumorigenesis

Summary/Abstract In transformed cells the demand to accumulate biomass requires substantial metabolic pathway alteration. Understanding this altered metabolism will enable identification of liabilities that can be exploited for cancer therapy. In prior work, we found that hyperoxic stress is a considerable force driving metabolic pathway dependence in breast cancer. Indeed, the enzyme most differentially required in high versus low oxygen environments, NFS1, is required for breast cancer metastasis to the lung. Moreover, NFS1 lies in an amplified region under positive selection in lung adenocarcinoma. Therefore, from prior work we conclude that the high oxygen environment of the lung is a key metabolic factor to which incipient breast metastases and lung tumors uniquely adapt, in part, via NFS1. Ours is the first work to describe a role for this critical pathway in cancer. The purpose of this grant is to gain mechanistic understanding of the NFS1 requirement, focusing on basal- like breast cancer (BLBC). NFS1 is a key enzyme in the biosynthesis of iron-sulfur clusters (ISC), essential cofactors in 48 proteins in humans. We found that BLBC cell lines are strikingly more sensitive than luminal lines to suppression of NFS1. We propose to identify the mechanistic underpinnings of this observation, and extend our findings to other cancer subtypes. We will suppress ISC containing proteins in a panel of breast cancer cell lines and verify which are differentially required in BLBC. Validated targets will be inhibited in xenograft-based models of breast cancer and metastasis to assess their impact on these processes. Many ISC containing genes are involved in the maintenance of genomic integrity. Our preliminary work reveals that NFS1 suppression results in the formation of double strand DNA breaks. These observations led us to suppress POLE, a key genomic integrity enzyme. Interestingly, suppression of POLE also blocks proliferation and induces double strand breaks in BLBC cell lines far more than luminal lines. Prior work has indicated that BLBC has defects in aspects of DNA repair that may sensitize them to therapy. Therefore we will suppress POLE and assess the impact on DNA replication, origin firing, replication fork stalling and restarting, and the repair of damaged replication forks. These experiments will contribute to our fundamental understanding of the sensitivity of BLBC to inhibition of DNA replication and induction of DNA damage. Finally, NFS1 suppression sensitizes cells to oxidative damage via a non-apoptotic form of cell death termed ferroptosis. Our findings lead to the intriguing possibility that activation of the iron-starvation response in iron-replete conditions, thereby tricking cancer cells into taking up excess iron, will render them highly susceptible to further oxidative stress and death by ferroptosis. By mechanistically understanding how best to activate the iron-starvation response downstream of NFS1, we anticipate that we will gain the benefit of inducing increased sensitivity to oxidants without having to target a generally cell-essential pathway.

摘要/摘要 在转化的细胞中，积累生物质的需求需要大量代谢途径改变。 了解这种改变的新陈代谢将能够确定可以利用癌症的负债 治疗。在先前的工作中，我们发现高氧化应激是驱动代谢途径的相当大的力 对乳腺癌的依赖。实际上，在高氧与低氧气中最差异的酶 乳腺癌转移到肺部需要环境NFS1。此外，NFS1位于放大 肺腺癌阳性选择的区域。因此，从先前的工作中，我们得出的结论是 肺的氧气环境是重要的代谢因素 独特地通过NFS1适应。我们的工作是描述癌症中这种关键途径的作用的第一项工作。 这笔赠款的目的是获得对NFS1要求的机械理解，重点是基础 像乳腺癌（BLBC）。 NFS1是铁硫簇（ISC）的生物合成的关键酶，必不可少的 人类48种蛋白质中的辅因子。我们发现BLBC细胞系比腔更敏感 抑制NFS1的线。我们建议确定该观察结果的机械基础，并 将我们的发现扩展到其他癌症亚型。我们将抑制含有蛋白质蛋白的ISC 癌细胞系并验证BLBC中需要的差异性。经过验证的目标将被抑制 基于异种移植的乳腺癌和转移模型，以评估它们对这些过程的影响。 许多包含ISC基因的基因组完整性涉及。我们的初步工作 表明NFS1抑制会导致双链DNA断裂的形成。这些观察结果 我们抑制POL，这是一种关键的基因组完整性酶。有趣的是，杆的抑制也阻塞 增殖和诱导双链在BLBC细胞系中的断裂远远超过腔线。先前的工作有 表明BLBC在DNA修复方面存在缺陷，这可能使它们对治疗敏感。因此，我们会的 抑制极点并评估对DNA复制，起源射击，复制叉的影响和重新启动的影响， 并修复受损的复制叉。这些实验将有助于我们的基本 了解BLBC对抑制DNA复制和诱导DNA损伤的敏感性。 最后，NFS1抑制细胞通过非凋亡形式的细胞死亡敏感 称为铁铁作用。我们的发现导致了激活铁饥饿反应的可能性 在铁的恢复条件下，欺骗癌细胞吸收了多余的铁，将使它们高度提高 容易受到进一步的氧化应激和螺旋病死亡的死亡。通过机械理解如何最好 激活NFS1下游的铁饥饿反应，我们预计我们将获得好处 诱导对氧化剂的敏感性增加，而不必靶向一般细胞的途径。