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:
- 金额:$ 35.87万
- 依托单位:
- 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:
- 关键词:Applications GrantsBindingBiologicalBreast Cancer CellBreast Cancer PatientCarnitineCell NucleusCell physiologyCellsCellular StressCombined Modality TherapyCommunicationConsumptionDataDependenceDevelopmentEndoplasmic ReticulumEnergy MetabolismEnhancersEnzymesFatty AcidsFunctional disorderGenetic TranscriptionGenetically Engineered MouseGoalsGrowthImpairmentIn VitroMediatingMembraneMetabolicMetabolic PathwayMitochondriaMolecularOncogenesOncogenicOrganellesPathway interactionsPatient-Focused OutcomesPilot ProjectsPredispositionProductionProteinsRelapseResearchResistanceRibonucleasesRoleSpecificityStressSwellingSystemic TherapyTestingTherapeuticToxic effectTransferaseTreatment EfficacyUpdateXBP1 genebiological adaptation to stressbreast cancer progressioncancer cellcancer subtypescell behaviorchemotherapycohortdocetaxelendoplasmic reticulum stressfatty acid oxidationimmunogenic cell deathimprovedin vivoinhibitorinsightlong chain fatty acidmalignant breast neoplasmmortalitynovelnovel therapeutic interventionoverexpressionparent grantpatient derived xenograft modelpharmacologicpre-clinicalprogramspromoterrelapse preventionresponserestraintsensorsynthetic lethal interactiontargeted treatmenttherapy resistanttriple-negative invasive breast carcinomatumortumor eradicationtumor growthtumor metabolismtumor xenografttumorigenesisuptake
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.
摘要
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。然而,在这方面,
潜在的机制,特别是癌基因依赖性代谢中细胞器间的通讯机制,
重新编程,在很大程度上是未知的。我们的初步研究表明,致癌MYC调节
内质网(ER)定位的跨膜传感器IRE 1a及其底物XBP 1通过多个
机制等重要的是,我们的初步研究表明,MYC过表达的三重基因的易感性增加,
IRE 1a/XBP 1抑制阴性乳腺癌(TNBC),可能通过改变细胞器间
通讯和代谢重编程脂肪酸氧化(粮农组织)。这些发现提供了一个
框架,以寻求对ER,线粒体和线粒体之间这种改变的通信的生物学见解。
细胞核中的MYC-过表达TNBC细胞,并进一步探索药理学抑制MYC的作用。
IRE 1a通过破坏细胞器间通讯作为MYC驱动的TNBC的抗肿瘤方法。我们
假设致癌MYC劫持ER应激传感器IRE 1a及其底物XBP 1,以促进
线粒体FAO和维持TNBC肿瘤发生和对化疗的抗性。这项建议会
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。目的1:研究IRE 1a/XBP 1的生物学意义
在MYC驱动的TNBC中介导的ER-核通讯。目标2将确定线粒体粮农组织的作用
在MYC驱动的TNBC中通过IRE 1 α/XBP 1途径激活。最后,目标3将研究体内疗效
以及IRE 1a抑制剂和多西他赛联合治疗MYC驱动的TNBC的机制。的
2年延长期的更新目标基于原始目标生成的数据,
代表了研究IRE 1介导的代谢重编程的原始目的的逻辑延伸,
细胞器功能障碍调节MYC驱动的TNBC的免疫原性细胞死亡。由此产生的数据
该提案将具有重要意义,因为它们将促进新的,基于机制的治疗方法的发展。
这些方法可以破坏这些改变的代谢途径并改善MYC驱动的TNBC的治疗。
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:
- 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:
- 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:
- 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。
- DOI:10.3389/fonc.2020.01100
- 发表时间:2020
- 期刊:
- 影响因子:4.7
- 作者:Xu,Longyong;Zhang,Weijie;Zhang,XiangH-F;Chen,Xi
- 通讯作者:Chen,Xi
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High-throughput closed-loop direct aberration sensing and correction for multiphoton imaging in live animals
用于活体动物多光子成像的高通量闭环直接像差传感和校正
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10572572 - 财政年份:2023
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