Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬-溶酶体系统来阻止胰腺癌
基本信息
- 批准号:10590682
- 负责人:
- 金额:$ 36.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAntigen PresentationAutophagocytosisAutophagosomeBRCA1 geneBindingBiochemistryBiogenesisCell LineCell membraneCell surfaceCellsComplexCoupledEndoplasmic ReticulumEndowmentEnsureEpitheliumEvolutionExcisionGeneticGoalsGolgi ApparatusGrantGrowthHumanImmuneImmune EvasionImmunofluorescence ImmunologicIn VitroLocationLysosomesMajor Histocompatibility ComplexMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMolecularMusNeoplasm MetastasisNormal CellOrganellesPancreasPancreatic Ductal AdenocarcinomaPancreatic Intraepithelial NeoplasiaPathway interactionsPatientsPeptidesPost-Translational Protein ProcessingProteinsProteomicsPublicationsRecyclingRoleRouteSamplingSpecimenStainsSurfaceSystemT-LymphocyteTestingTissue BanksTumor TissueUbiquitinWorkcancer cellfitnessgenetic approachimmune checkpoint blockadeimmunogenicityin vivometabolic fitnessmouse modelnovelpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpeptide Iprotein degradationreceptortraffickingtumorubiquitin ligase
项目摘要
PROJECT SUMMARY
Cancer cells co-opt autophagy - an evolutionarily conserved cellular recycling pathway - to maintain
metabolic fitness. Prior studies have shown that Pancreatic Ductal Adenocarcinoma (PDA) up-regulates
autophagy and lysosomes – acidic organelles where autophagic cargo is degraded – to dramatically increase
the bulk breakdown and recycling of diverse intracellular substrates. An additional, less well understood
function of autophagy is the selective removal of specific proteins in order to endow PDA cells with
enhanced fitness.
We now show that the autophagy-lysosome pathway selectively targets major histocompatibility
complex class I (MHC-I) protein for degradation as a mechanism of immune evasion. Through affinity-
based capture of intact lysosomes (LysoIP) from normal and PDA cell lines coupled with proteomics-based
analysis, we identified MHC-I as a significantly enriched lysosomal substrate in PDA cells. Consistent with this
finding, immuno-fluorescence staining demonstrates that, unlike normal cells where MHC-I localizes to the
plasma membrane (PM), in PDA cell lines and primary patient PDA specimens, MHC-I is trapped inside
autophagosomes and lysosomes. Importantly, tumor-specific suppression of autophagy is sufficient to 1)
stabilize and re-localize MHC-I to the PM, 2) increase antigen presentation and 3) boost T cell mediated tumor
killing in vitro and in vivo. Building on these findings the goal of this study is to determine the molecular
mechanisms underlying aberrant MHC-I trafficking, and to identify targetable nodes that can be manipulated to
restore MHC-I on the cell surface of PDA cells. Our revised application will leverage the combined power of
biochemistry, genetics, organelle purification and proteomics, a novel mouse model and patient PDA samples
to address the following specific aims: 1) determine how post-translational modifications of MHC-I cooperate
with the autophagy machinery to facilitate capture by autophagosomes, 2) identify where along its trafficking
route is MHC-I diverted to autophagosomes and 3) determine when during the course of PDA evolution does
MHC-I dysregulation occur and can we exploit this information to establish more effective strategies to enhance
antigen presentation and immune mediated tumor killing.
In summary, our discovery of autophagy dependent degradation of MHC-I highlights an important new
paradigm for immune evasion in PDA and potentially other cancers. Findings from our proposed studies will
determine key molecular mechanisms underlying MHC-I dysregulation and establish new nodes that can be
targeted to restore antigen presentation in PDA.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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Rushika Miriam Perera其他文献
Rushika Miriam Perera的其他文献
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{{ truncateString('Rushika Miriam Perera', 18)}}的其他基金
Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬溶酶体系统来阻止胰腺癌
- 批准号:
10212065 - 财政年份:2021
- 资助金额:
$ 36.49万 - 项目类别:
Targeting the autophagy-lysosome system to block pancreatic cancer
靶向自噬-溶酶体系统来阻止胰腺癌
- 批准号:
10358483 - 财政年份:2021
- 资助金额:
$ 36.49万 - 项目类别:
Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
- 批准号:
10594038 - 财政年份:2021
- 资助金额:
$ 36.49万 - 项目类别:
Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
- 批准号:
10186267 - 财政年份:2021
- 资助金额:
$ 36.49万 - 项目类别:
Dissecting new mechanisms of lysosome quality control in health and disease
剖析健康和疾病中溶酶体质量控制的新机制
- 批准号:
10370440 - 财政年份:2021
- 资助金额:
$ 36.49万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
10404053 - 财政年份:2020
- 资助金额:
$ 36.49万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
10626914 - 财政年份:2020
- 资助金额:
$ 36.49万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
10252885 - 财政年份:2020
- 资助金额:
$ 36.49万 - 项目类别:
Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer
识别胰腺癌细胞可塑性的分子驱动因素
- 批准号:
9974205 - 财政年份:2020
- 资助金额:
$ 36.49万 - 项目类别:
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