Decoding and targeting saccharopine pathway in cancer metastasis

解码和靶向癌症转移中的糖碱途径

基本信息

批准号：
10344916
负责人：
Sumin Kang
金额：
$ 41.98万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10344916
关键词：
Attenuated Binding Proteins Biological Assay Cancer Patient Cancer cell line Cause of Death Cells Clinical Custom Data Development Disseminated Malignant Neoplasm Down-Regulation Enzymes Equilibrium FDA approved Gene set enrichment analysis Genes Genomics Glean HGF gene Head Cancer Head and Neck Cancer Homeostasis Human In Vitro Libraries Link Lung Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Mediating Metabolic Metastatic to Mitochondria Molecular Neck Cancer Neoplasm Metastasis Oxidation-Reduction Pathway interactions Patients Phosphotransferases Play Prognostic Marker Proteins RNA Interference RNA Splicing RNA interference screen Research Series Signal Pathway Signal Transduction Solid Neoplasm TXN gene Tannic Acid Treatment Efficacy Tumor Tissue Up-Regulation Variant XBP1 gene Xenograft procedure activating transcription factor cancer cell cancer therapy cancer type cohort in vivo inhibitor insight kinase inhibitor malignant breast neoplasm neoplastic cell novel patient derived xenograft model saccharopine small hairpin RNA small molecule therapeutic target transcription factor transcriptome sequencing transcriptomics tumor upstream kinase

项目摘要

Growing evidence suggests that cancer cells undergo significant metabolic alterations during metastasis. Recent studies show that functional mitochondria are essential for the tumor cell development. However, we largely do not know how mitochondrial factors contribute to metastatic progression. To identify a novel mitochondrial factor critical for cancer metastasis, we performed an unbiased RNAi-based screen using a customized RNAi library targeting 120 mitochondrial enzymes. Screen using various types of cancer cells reveled that aminoadipate- semialdehyde synthase (AASS) in the saccharopine pathway is a common critical factor for the invasion. In vitro and in vivo study using AASS variants demonstrated that the activity of AASS is required for cancer cell invasion and metastasis. Targeting each of the enzymes in the saccharopine pathway revealed 2-aminoadipate (2-AAA), a metabolic intermediate, as a key factor for cell invasion. Metabolic, genomic, and transcriptomics approaches were made to gain mechanistic insight into AASS in cancer metastasis. Through a series of metabolic assays, we found that AASS promotes invasion by managing redox homeostasis in lung and head/neck cancers. Genomic profiling and GSEA showed that AASS loss results in decrease of peroxisomal genes and a redox protein TXNDC5. Moreover, spliced form of XBP1, an activated transcription factor of TXNDC5, was reduced in cells that lack AASS, suggesting a potential link among AASS, sXBP1, and TXNDC5. In addition, through a kinase inhibitor profiling and comprehensive transcription factor profiling, we identified upstream regulators of AASS. In particular, we found HGF/c-MET as a kinase and an activator of AASS, and SATB1 as a potential transcription factor of AASS. Furthermore, our preliminary data showed that AASS upregulation positively correlates with metastatic progression in tumor tissues from cancer patients, suggesting AASS as a promising prognostic marker and a therapeutic target to treat metastatic cancers. Therefore, we screened and identified a US FDA approved compound tannic acid as a potent AASS inhibitor and an anti-metastasis agent. Our central hypothesis is that AASS and its metabolic intermediate 2-AAA provide metastastic signals through their potential regulators and effectors in cancer cells. Thus, AASS signaling represents a promising anti-metastasis target in human cancers. We will use lung cancer and head and neck cancer as a research platform to validate AASS signaling as a common metastasis driver. Three specific aims are proposed: (1) To decipher the molecular mechanism underlying AASS-XBP1 activation, which manages redox signaling and confers metastatic potential in human cancer; (2) To determine how AASS is activated and induced by HGF/c- MET and SATB1 to mediate metastasis; (3) To validate AASS as a therapeutic target in treatment of metastatic cancers using the novel AASS inhibitor tannic acid.

越来越多的证据表明癌细胞在转移过程中经历显着的代谢改变。最近的研究表明，功能性线粒体对于肿瘤细胞的发育至关重要。然而，我们很大程度上做不知道线粒体因素如何促进转移进展。鉴定一种新的线粒体因子对于癌症转移至关重要，我们使用定制的 RNAi 库进行了基于 RNAi 的公正筛选针对 120 种线粒体酶。使用各种类型的癌细胞进行的筛选表明，氨基己二酸- 糖苷途径中的半醛合酶（AASS）是入侵的常见关键因素。体外使用 AASS 变体的体内研究表明，AASS 的活性是癌细胞侵袭所必需的和转移。针对糖苷途径中的每种酶发现 2-氨基己二酸 (2-AAA)，代谢中间体，作为细胞侵袭的关键因素。代谢、基因组和转录组学方法旨在深入了解 AASS 在癌症转移中的机制。通过一系列的代谢检测，我们发现 AASS 通过管理肺癌和头颈癌的氧化还原稳态来促进侵袭。基因组分析和 GSEA 显示 AASS 损失导致过氧化物酶体基因和氧化还原减少蛋白质TXNDC5。此外，XBP1（TXNDC5 的一种激活转录因子）的剪接形式在缺乏 AASS 的细胞，表明 AASS、sXBP1 和 TXNDC5 之间存在潜在联系。此外，通过一个通过激酶抑制剂分析和综合转录因子分析，我们确定了上游调节因子美国科学院院士。特别是，我们发现 HGF/c-MET 作为 AASS 的激酶和激活剂，而 SATB1 作为潜在的 AASS 转录因子。此外，我们的初步数据表明 AASS 上调积极与癌症患者肿瘤组织的转移进展相关，表明 AASS 是一种有前途的方法预后标志物和治疗转移性癌症的治疗靶点。因此，我们筛选并确定了美国 FDA 批准复方单宁酸作为有效的 AASS 抑制剂和抗转移剂。我们的中心假设是 AASS 及其代谢中间体 2-AAA 提供转移信号通过癌细胞中潜在的调节因子和效应因子。因此，AASS 信号代表了一种有前途的信号人类癌症的抗转移靶点。我们将使用肺癌和头颈癌作为研究对象验证 AASS 信号作为常见转移驱动因素的平台。提出了三个具体目标： (1) 破译 AASS-XBP1 激活的分子机制，该机制管理氧化还原信号传导并赋予人类癌症转移潜力； (2) 确定HGF/c-如何激活和诱导AASS MET 和 SATB1 介导转移； (3) 验证AASS作为治疗转移性肿瘤的治疗靶点使用新型 AASS 抑制剂单宁酸治疗癌症。