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，情境和癌基因依赖性的。然而，基本机制，尤其是依赖癌基因代谢中的生产机制的机制重编程，在很大程度上未知。我们的初步研究表明，致癌MYC调节内质网（ER） - 局部跨膜传感器IRE1A及其底物XBP1通过多个机制。重要的是，我们的试点研究表明，过表达MYC的三重乳腺癌（TNBC）对IRE1A/XBP1抑制作用，可能通过改变的跨加工通信和代谢重编程与脂肪酸氧化（FAO）。这些发现提供了框架寻求生物学洞察力，以了解ER，线粒体和在过表达MYC的TNBC细胞中的核，并进一步探索药物抑制的影响 IRE1A是通过破坏跨加工的通信，是MYC驱动的TNBC的一种抗肿瘤方法。我们假设致癌MYC劫持了ER应力传感器IRE1A及其底物XBP1，以促进线粒体粮农组织并维持TNBC肿瘤发生和对化学疗法的抗性。该提议将阐明ER在控制MYC驱动的致癌应力和线粒体方面的功能和机制 TNBC中的代谢重编程。在AIM 1中，我们将研究IRE1A/XBP1的生物学性 MYC驱动的TNBC中介导的ER核路通信。 AIM 2将确定线粒体粮农组织的作用 MYC驱动的TNBC中IRE1α/XBP1途径的激活。最后，AIM 3将研究体内效率与IRE1A抑制剂和多西他赛在治疗MYC驱动的TNBC中的组合疗法的机制和机制。这 2年延长期更新的目标是基于原始目的产生的数据和代表原始目的的逻辑扩展，以研究IRE1介导的代谢重编程和细胞器功能障碍在调节MYC驱动的TNBC的免疫原性死亡中。从中产生的数据提案将很重要，因为它们将促进基于机制的新型治疗的发展破坏这些改变的代谢途径并改善MYC驱动TNBC的治疗方法的方法。

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.

DOI：
10.1186/s13059-021-02464-2
发表时间：
2021-08-23
期刊：
Genome biology
影响因子：
12.3
作者：
Sun M;Wang Y;Zheng C;Wei Y;Hou J;Zhang P;He W;Lv X;Ding Y;Liang H;Hon CC;Chen X;Xu H;Chen Y
通讯作者：
Chen Y

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

DOI：
10.1038/s41467-020-20492-7
发表时间：
2021-01-15
期刊：
Nature communications
影响因子：
16.6
作者：
Xu J;Shi J;Cui X;Cui Y;Li JJ;Goel A;Chen X;Issa JP;Su J;Li W
通讯作者：
Li W

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

DOI：
10.1172/jci159940
发表时间：
2023-03-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Zheng, Caishang;Wei, Yanjun;Zhang, Peng;Xu, Longyong;Zhang, Zhenzhen;Lin, Kangyu;Hou, Jiakai;Lv, Xiangdong;Ding, Yao;Chiu, Yulun;Jain, Antrix;Islam, Nelufa;Malovannaya, Anna;Wu, Yun;Ding, Feng;Xu, Han;Sun, Ming;Chen, Xi;Chen, Yiwen
通讯作者：
Chen, Yiwen

Endoplasmic Reticulum Stress in Bone Metastases.

骨转移中的内质网应力。