Therapeutic Targeting of Autophagey-Dependent Cancer
自噬依赖性癌症的治疗靶向
基本信息
- 批准号:10654945
- 负责人:
- 金额:$ 8.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-11 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAftercareAnimalsAntineoplastic AgentsAntioxidantsApoptosisApoptoticAutophagocytosisBindingBiological AssayBiologyCRISPR/Cas technologyCancer cell lineCatabolic ProcessCell DeathCell LineCell SurvivalCell physiologyCellsCellular biologyChemosensitizationClinicClinical TreatmentClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsDataDependenceExcisionFoundationsGenesGrowthHomeostasisHumanIn VitroKnock-outKnowledgeLinkLysosomesMalignant NeoplasmsMediatingMentorsMentorshipMethodsMicroscopyMitochondriaMitochondrial ProteinsMusParkinPharmaceutical PreparationsPhasePredispositionProcessProteinsPublishingRecyclingRegulationReportingResearchResistanceResolutionRoleSignal TransductionStressTechniquesTestingToxinTrainingUp-RegulationVesicleWorkcancer cellchemotherapeutic agentchemotherapyimprovedinhibition of autophagyinhibitorinsightknock-downneoplastic cellnoveloptogeneticspre-clinicalpreclinical studypressurepro-apoptotic proteinprogramsproteostasisresistance mechanismresponsetargeted treatmenttherapeutic targettumortumorigenic
项目摘要
Project Summary/Abstract
Autophagy is an essential catabolic process that cells rely on to breakdown cytoplasmic constituents.
In-vitro and pre-clinical animal studies indicate a pro-tumorigenic role for autophagy, leading to the launch of
over 60 clinical trials utilizing autophagy inhibition. Initial results from clinical trials have been promising,
however, these studies already indicate both inherent and acquired resistance to autophagy inhibition in
certain tumors. I hypothesize that understanding how tumors circumvent autophagy inhibition will
improve the use of autophagy-targeted therapeutics. In my recently published studies, I created a dynamic,
Live-Cell CRISPR/Cas9 assay (LC-CRISPR) to target 12 core autophagy genes in a panel of 8 cancer cell
lines. I identified autophagy dependent cell lines, however, I also discovered that, with enough selective
pressure, even highly autophagy dependent cells can survive loss of autophagy – specifically loss of the core
autophagy proteins ATG7 and FIP200. I discovered that the newly-acquired, autophagy-independent, ATG7-/-
and FIP200-/- cells acquired an increased dependence on NRF2 cytoprotective and antioxidant signaling to
maintain protein homeostasis. My initial studies also suggest the ATG7-/- and FIP200-/- cells have increased
additional cytoprotective processes such as mitochondrial fusion and mitochondrial derived vesicles (MDVs).
Previous reports have linked autophagy and NRF2 signaling, however, this will be the first study to
understand the role of NRF2 in dictating autophagy dependence. These studies will utilize novel techniques
that I have developed including LC-CRISPR and rapid optogenetic inhibition of autophagy to understand the
necessity and sufficiency, as well as the in-depth mechanism, rate, and duration of NRF2 antioxidant signaling
in mediating autophagy dependence in cancer. I hypothesize that NRF2 expression, both basal and
induced expression after autophagy inhibition will dictate autophagy dependence in cancer cells.
The 2nd aim and 3rd aims will utilize the isogeneic autophagy dependent WT and ATG7-/- and FIP200-/-
autophagy-independent cell lines as well as Atg5-/- mouse tumor cells that circumvented autophagy inhibition in
a live animal to understand the links between autophagy dependence, apoptosis, and mitochondrial dynamics.
In a previous study we identified the critical link between autophagy and apoptosis and showed that autophagy
inhibition leads to increased FOXO3a binding to PUMA and increases sensitivity to other chemotherapeutic
agents. The studies proposed here will test the hypothesis that cells that circumvent autophagy
dependence also circumvent the FOXO3a-PUMA mediated link between autophagy and apoptosis due
to increased mitochondrial fusion. The final aim will test the hypothesis that MDVs are critical for the
removal of damaged portions of mitochondria independent of canonical mitophagy and this activity
therefore maintains mitochondrial homeostasis. Together these studies will elucidate how cancer cells can
circumvent autophagy dependence and provide insight into mechanisms of resistance to autophagy inhibition.
!
项目总结/摘要
自噬是一个重要的分解代谢过程,细胞依靠它来分解细胞质成分。
体外和临床前动物研究表明自噬具有促肿瘤作用,从而导致了
超过60个利用自噬抑制的临床试验。临床试验的初步结果是有希望的,
然而,这些研究已经表明,
某些肿瘤我假设,了解肿瘤如何规避自噬抑制,
改善自噬靶向治疗的使用。在我最近发表的研究中,我创造了一个动态的,
活细胞CRISPR/Cas9测定(LC-CRISPR)靶向一组8个癌细胞中的12个核心自噬基因
线我鉴定了自噬依赖性细胞系,然而,我还发现,如果有足够的选择性,
即使是高度自噬依赖的细胞,也可以在失去自噬后存活-特别是失去核心细胞。
自噬蛋白ATG 7和FIP 200。我发现新获得的,不依赖自噬的,ATG 7-/-
FIP 200-/-细胞获得了对NRF 2细胞保护和抗氧化信号的依赖性增加,
维持蛋白质稳态。我的初步研究还表明,ATG 7-/-和FIP 200-/-细胞增加了,
另外的细胞保护过程,例如线粒体融合和线粒体衍生的囊泡(MDV)。
以前的报道已经将自噬和NRF 2信号联系起来,然而,这将是第一项研究,
了解NRF 2在决定自噬依赖性中的作用。这些研究将利用新技术
包括LC-CRISPR和自噬的快速光遗传学抑制,
必要性和充分性,以及NRF 2抗氧化信号传导的深入机制,速率和持续时间
介导癌症中的自噬依赖。我假设NRF 2的表达,无论是基础的,
自噬抑制后诱导的表达将决定癌细胞中的自噬依赖性。
第二个目标和第三个目标将利用同源自噬依赖性WT和ATG 7-/-和FIP 200-/-
自噬非依赖性细胞系以及Atg 5-/-小鼠肿瘤细胞,这些细胞绕过了自噬抑制,
一个活的动物,以了解自噬依赖,凋亡和线粒体动力学之间的联系。
在以前的研究中,我们确定了自噬和凋亡之间的关键联系,并表明自噬
抑制导致FOXO 3a与PUMA的结合增加,并增加对其他化疗药物的敏感性
剂.这里提出的研究将验证这样一个假设,即绕过自噬的细胞
依赖性也绕过FOXO 3a-BRA介导的自噬和凋亡之间的联系,
增加线粒体融合最终目的将检验MDV对以下假设的重要性:
线粒体损伤部分的去除不依赖于典型的线粒体自噬,
从而维持线粒体的稳态。这些研究将共同阐明癌细胞如何
规避自噬依赖性,并提供对自噬抑制抗性机制的深入了解。
!
项目成果
期刊论文数量(0)
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专利数量(0)
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Christina G Towers其他文献
Christina G Towers的其他文献
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{{ truncateString('Christina G Towers', 18)}}的其他基金
Tracking the Mechanisms of Adaptation to Autophagy Inhibition
追踪自噬抑制的适应机制
- 批准号:
10685861 - 财政年份:2023
- 资助金额:
$ 8.26万 - 项目类别:
Therapeutic Targeting of Autophagey-Dependent Cancer
自噬依赖性癌症的治疗靶向
- 批准号:
10451999 - 财政年份:2020
- 资助金额:
$ 8.26万 - 项目类别:
Therapeutic Targeting of Autophagey-Dependent Cancer
自噬依赖性癌症的治疗靶向
- 批准号:
10472048 - 财政年份:2020
- 资助金额:
$ 8.26万 - 项目类别:
Therapeutic Targeting of Autophagey-Dependent Cancer
自噬依赖性癌症的治疗靶向
- 批准号:
10657567 - 财政年份:2020
- 资助金额:
$ 8.26万 - 项目类别:
Therapeutic Targeting of Autophagey-Dependent Cancer
自噬依赖性癌症的治疗靶向
- 批准号:
10054905 - 财政年份:2020
- 资助金额:
$ 8.26万 - 项目类别:
Therapeutic Targeting of Autophagy-Dependent Cancer
自噬依赖性癌症的治疗靶向
- 批准号:
10533694 - 财政年份:2020
- 资助金额:
$ 8.26万 - 项目类别:
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