Targeting Metabolic Liabilities in Cancer

针对癌症的代谢负担

基本信息

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
项目类别：
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

项目摘要

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/摘要在转化细胞中，积累生物量的需求需要大量的代谢途径改变。了解这种新陈代谢的改变将有助于识别可用于治疗癌症的因素治疗。在之前的工作中，我们发现高氧应激是驱动代谢途径的重要力量乳腺癌的依赖性。事实上，高氧和低氧环境下所需的酶差异最大 NFS1 是乳腺癌转移至肺部所必需的环境。此外，NFS1 存在于一个放大的肺腺癌中正选择区域。因此，根据之前的工作，我们得出的结论是，高肺的氧环境是早期乳腺转移和肺部肿瘤的关键代谢因素部分通过 NFS1 进行独特的适应。我们的工作是第一篇描述这一关键途径在癌症中的作用的工作。这笔赠款的目的是获得对 NFS1 要求的机械理解，重点是基础如乳腺癌（BLBC）。 NFS1 是铁硫簇 (ISC) 生物合成中的关键酶，对于铁硫簇 (ISC) 至关重要人类 48 种蛋白质的辅因子。我们发现 BLBC 细胞系比 Luminal 细胞系更加敏感线抑制 NFS1。我们建议确定这一观察的机制基础，并且将我们的发现扩展到其他癌症亚型。我们将抑制一组乳房中含有蛋白质的 ISC 癌细胞系并验证 BLBC 中所需的差异。已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。许多含有 ISC 的基因参与基因组完整性的维护。我们的前期工作揭示 NFS1 抑制导致双链 DNA 断裂的形成。这些观察导致我们来抑制 POLE，一种关键的基因组完整性酶。有趣的是，抑制 POLE 也会阻止 BLBC 细胞系中的增殖和诱导双链断裂的程度远高于 luminal 细胞系。之前的工作有表明 BLBC 在 DNA 修复方面存在缺陷，这可能会使他们对治疗敏感。因此我们将抑制 POLE 并评估对 DNA 复制、起源激发、复制叉停止和重新启动的影响，以及修复受损的复制叉。这些实验将有助于我们的基础研究了解 BLBC 对 DNA 复制抑制和 DNA 损伤诱导的敏感性。最后，NFS1 抑制通过非凋亡形式的细胞死亡使细胞对氧化损伤敏感称为铁死亡。我们的发现导致了一个有趣的可能性，即铁饥饿反应的激活在铁充足的条件下，从而诱使癌细胞吸收过量的铁，将使它们高度容易受到进一步的氧化应激并因铁死亡而死亡。通过机械地理解如何最好地激活 NFS1 下游的铁饥饿反应，我们预计我们将获得以下好处诱导对氧化剂的敏感性增加，而不必针对一般的细胞必需途径。