Crosstalk between the ER Stress Response and Mitochondrial Fatty Acid Oxidation in MYC-driven Breast Cancer

MYC 驱动的乳腺癌中 ER 应激反应与线粒体脂肪酸氧化之间的串扰

基本信息

批准号：
10581179
负责人：
Xi Chen
金额：
$ 35.87万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581179
关键词：
Applications Grants Binding Biological Breast Cancer Cell Breast Cancer Patient Carnitine Cell Nucleus Cell physiology Cells Cellular Stress Combined Modality Therapy Communication Consumption Data Dependence Development Endoplasmic Reticulum Energy Metabolism Enhancers Enzymes Fatty Acids Functional disorder Genetic Transcription Genetically Engineered Mouse Goals Growth Impairment In Vitro Mediating Membrane Metabolic Metabolic Pathway Mitochondria Molecular Oncogenes Oncogenic Organelles Pathway interactions Patient-Focused Outcomes Pilot Projects Predisposition Production Proteins Relapse Research Resistance Ribonucleases Role Specificity Stress Swelling Systemic Therapy Testing Therapeutic Toxic effect Transferase Treatment Efficacy Update XBP1 gene biological adaptation to stress breast cancer progression cancer cell cancer subtypes cell behavior chemotherapy cohort docetaxel endoplasmic reticulum stress fatty acid oxidation immunogenic cell death improved in vivo inhibitor insight long chain fatty acid malignant breast neoplasm mortality novel novel therapeutic intervention overexpression parent grant patient derived xenograft model pharmacologic pre-clinical programs promoter relapse prevention response restraint sensor synthetic lethal interaction targeted treatment therapy resistant triple-negative invasive breast carcinoma tumor tumor eradication tumor growth tumor metabolism tumor xenograft tumorigenesis uptake

项目摘要

ABSTRACT It is well known that cancer metabolism is highly dynamic and context- and oncogene-dependent. However, the underlying mechanism, particularly that of interorganelle communication in oncogene-dependent metabolic reprogramming, is largely unknown. Our preliminary studies establish that oncogenic MYC regulates Endoplasmic Reticulum (ER)-localized transmembrane sensor IRE1a and its substrate XBP1 via multiple mechanisms. Importantly, our pilot studies suggest the increased susceptibility of MYC-overexpressing triple negative breast cancer (TNBC) to IRE1a/XBP1 inhibition, possibly mediated via altered interorganelle communication and metabolic reprogramming to fatty acid oxidation (FAO). These findings provide a framework to seek biological insight into this altered communication between the ER, mitochondria, and nucleus in MYC-overexpressing TNBC cells, and to further explore the effects of pharmacological inhibition of IRE1a as an anti-tumor approach for MYC-driven TNBC by disrupting the interorganelle communication. We hypothesize that oncogenic MYC hijacks the ER stress sensor IRE1a, and its substrate XBP1, to promote mitochondrial FAO and sustain TNBC tumorigenesis and resistance to chemotherapy. This proposal will elucidate the function and mechanism of the ER in regulating MYC-driven oncogenic stress and mitochondrial metabolic reprogramming in TNBC. In Aim 1, we will investigate the biological significance of IRE1a/XBP1 mediated ER-nucleus communication in MYC-driven TNBC. Aim 2 will determine the role of mitochondrial FAO activation by the IRE1α/XBP1 pathway in MYC-driven TNBC. Lastly, Aim 3 will investigate the in vivo efficacy and mechanisms of combination therapy with IRE1a inhibitor and docetaxel in treating MYC-driven TNBC. The updated Aims for the 2-year extension period are based on the data generated from the original aims and represent a logical extension of the original aims to study the IRE1-mediated metabolic reprogramming and organelle dysfunction in regulating immunogenic cell death of MYC-driven TNBC. The resulting data from this proposal will be significant as they will promote the development of novel, mechanism-based therapeutic approaches to disrupt these altered metabolic pathways and improve the treatment of MYC-driven TNBC.

抽象的众所周知，癌症代谢是高度动态的并且依赖于背景和癌基因。潜在的机制，特别是癌基因依赖性代谢中细胞器间通讯的机制我们的初步研究表明，致癌性 MYC 的调控在很大程度上是未知的。内质网（ER）定位的跨膜传感器IRE1a及其底物XBP1通过多个重要的是，我们的初步研究表明 MYC 过表达三联体的易感性增加。阴性乳腺癌 (TNBC) 对 IRE1a/XBP1 的抑制，可能是通过细胞器间改变介导的这些发现提供了脂肪酸氧化的通讯和代谢重编程。框架来寻求生物学见解来了解内质网、线粒体和 MYC过表达TNBC细胞中的细胞核，并进一步探讨药理学抑制作用 IRE1a 通过破坏细胞间通讯作为 MYC 驱动的 TNBC 的抗肿瘤方法。致癌 MYC 劫持 ER 应激传感器 IRE1a 及其底物 XBP1，以促进线粒体FAO和维持TNBC肿瘤发生和化疗耐药性。阐明 ER 在调节 MYC 驱动的致癌应激和线粒体中的功能和机制 TNBC 中的代谢重编程在目标 1 中，我们将研究 IRE1a/XBP1 的生物学意义。 MYC 驱动的 TNBC 中介导的 ER 核通讯将决定线粒体 FAO 的作用。最后，Aim 3 将研究 MYC 驱动的 TNBC 中 IRE1α/XBP1 通路的激活。以及 IRE1a 抑制剂和多西紫杉醇联合治疗 MYC 驱动的 TNBC 的机制。两年延长期的更新目标是基于原始目标生成的数据和代表了研究 IRE1 介导的代谢重编程的原始目标的逻辑延伸细胞器功能障碍调节 MYC 驱动的 TNBC 的免疫原性细胞死亡。该提案将具有重要意义，因为它们将促进新型基于机制的治疗方法的开发破坏这些改变的代谢途径并改善 MYC 驱动的 TNBC 治疗的方法。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systematic functional interrogation of human pseudogenes using CRISPRi.

使用 CRISPRi 对人类假基因进行系统功能询问。

DOI：
发表时间：
2021-08-23
期刊：
影响因子：
12.3
作者：
Sun, Ming;Wang, Yunfei;Zheng, Caishang;Wei, Yanjun;Hou, Jiakai;Zhang, Peng;He, Wei;Lv, Xiangdong;Ding, Yao;Liang, Han;Hon, Chung;Chen, Xi;Xu, Han;Chen, Yiwen
通讯作者：
Chen, Yiwen

Cellular Heterogeneity-Adjusted cLonal Methylation (CHALM) improves prediction of gene expression.

细胞异质性调整克隆甲基化 (CHALM) 改善了基因表达的预测。

DOI：
发表时间：
2021
期刊：
影响因子：
16.6
作者：
Xu, Jianfeng;Shi, Jiejun;Cui, Xiaodong;Cui, Ya;Li, Jingyi Jessica;Goel, Ajay;Chen, Xi;Issa, Jean;Su, Jianzhong;Li, Wei
通讯作者：
Li, Wei

Endoplasmic Reticulum Stress in Bone Metastases.

骨转移中的内质网应力。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Xu, Longyong;Zhang, Weijie;Zhang, Xiang H;Chen, Xi
通讯作者：
Chen, Xi

CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer.

CRISPR/Cas9 筛选揭示了人类癌症中隐秘 lncRNA 编码的开放阅读框的功能翻译。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
0
作者：
Zheng, Caishang;Wei, Yanjun;Zhang, Peng;Xu, Longyong;Zhang, Zhenzhen;Lin, Kangyu;Hou, Jiakai;Lv, Xiangdong;Ding, Yao;Chiu, Yulun;Jain, Antri;Islam, Nelufa;Malovannaya, Anna;Wu, Yun;Ding, Feng;Xu, Han;Sun, Ming;Chen, Xi;Chen, Yiwen
通讯作者：
Chen, Yiwen