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
基本信息
- 批准号:10404053
- 负责人:
- 金额:$ 36.2万
- 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:2020-09-03 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAutomobile DrivingBiologyCancer EtiologyCell LineCellsCessation of lifeClassificationClinicCoculture TechniquesDiseaseEffectivenessEpithelial CellsErinaceidaeGLI2 geneGene Expression ProfilingGeneticGenetic TranscriptionGoalsHumanKRAS2 geneLigandsMaintenanceMalignant neoplasm of pancreasMediatingMetastatic toModelingMolecularMusNeoplasm MetastasisOutcomePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPharmacologyPhenotypePrimary NeoplasmProcessPrognosisRelapseResectedResistanceRoleSpecimenUp-RegulationVariantWestern WorldWorkautocrinechemotherapyclinically relevantcombatconditioningdisorder subtypeeffective therapygain of functionhuman modelin vivomutantneoplastic cellosteopontinoverexpressionpancreatic ductal adenocarcinoma cellparacrineprogramsresistance mechanismtargeted treatmenttranscription factortreatment responsetumortumor growthtumor progressiontumorigenic
项目摘要
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive disease that is projected to become the second
leading cause of cancer deaths in the Western world by 2030. Recently, studies utilizing transcriptional profiling
from resected PDA specimens have identified two molecularly distinct subtypes termed Classical and Basal.
These subtypes correlate with overall patient survival, with the Basal subtype predictive of higher rates of
metastasis, poor response to therapy and the worst outcomes. While this classification represents an important
breakthrough for identifying patients with the most aggressive variant of PDA, the underlying circuits that drive
key features of this variant are unknown. Without a clear understanding of this biology, our ability to effectively
treat patients with the deadliest form of PDA is compromised. Thus, a major goal in the field is to identify drivers
of the Classical and Basal subtypes of PDA in order to 1) effectively target Basal PDA or 2) promote conversion
to a less aggressive variant (Classical) that may respond more effectively to therapy.
Towards this goal, we have discovered that the Hedgehog pathway transcription factor, GLI2, functions
in a non-canonical ligand independent manner as a critical regulator of the most aggressive Basal subtype of
PDA (Adams et al eLife, 2019; PMC6538376). The key findings in support of this model are, (1) GLI2 expression
is elevated in Basal PDA cell lines and patient tumors and predicts shorter survival in patients, (2) GLI2
suppression leads to loss of Basal identity and inhibits tumor growth while ectopic GLI2 expression in Classical
PDA cells causes a switch to the Basal state (3). Our findings underscore a previously unrecognized level of
plasticity in PDA cells and highlight an entirely new role for GLI2 in driving Basal identity in this disease. Building
on this work, we hypothesize that suppression of GLI2 represents a unique vulnerability in Basal PDA to
combat KRAS* resistance and tumor progression. Thus, we propose 2 specific aims that will 1) define the
non-canonical transcriptional circuits regulated by GLI2 in a cell-autonomous manner to mediate resistance to
KRAS* pathway suppression and 2) determine how GLI2-dependent secreted factors condition surrounding cells
to promote primary and metastatic tumor growth. These studies will determine the cellular circuits that control
Basal identity, define their role in the context of KRAS* resistance, tumor relapse and metastasis and lay the
groundwork for increasing the effectiveness of KRAS-targeted therapies that have entered the clinic.
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)
会议论文数量(0)
专利数量(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:
$ 36.2万 - 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:
$ 36.2万 - 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:
10590682 - 财政年份:2021
- 资助金额:
$ 36.2万 - 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:
$ 36.2万 - 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:
$ 36.2万 - 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:
$ 36.2万 - 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:
$ 36.2万 - 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:
$ 36.2万 - 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:
$ 36.2万 - 项目类别:
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