Cellular phenotypic heterogeneity and resistance to radiotherapy in pancreatic adenocarcinoma
胰腺腺癌的细胞表型异质性和放疗耐药性
基本信息
- 批准号:10693293
- 负责人:
- 金额:$ 39.38万
- 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:2021-09-22 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcyltransferaseAddressAdultAnimal ExperimentationAnimalsAwardBiochemicalBiologicalBiological AssayCancer BiologyCareer MobilityCell Differentiation processCellsCharacteristicsChemotherapy and/or radiationClinicClinicalClinical ManagementColorectal AdenocarcinomaCore FacilityDataEligibility DeterminationEnzymesEpigenetic ProcessEvolutionFacultyGene Expression ProfilingGeneticGenetic HeterogeneityGenetically Engineered MouseGoalsHeterogeneityHumanImmunocompetentImmunotherapyIndividualInstitutionLGR5 geneLaboratoriesLaboratory ResearchLettersLigandsLocalized DiseaseLung AdenocarcinomaMalignant NeoplasmsMalignant neoplasm of pancreasMemorial Sloan-Kettering Cancer CenterMentorsMethodsMinorityMolecularMusOperative Surgical ProceduresPancreasPancreatic AdenocarcinomaPancreatic Ductal AdenocarcinomaPancreatic InjuryPathway interactionsPatientsPhenotypePopulationPorcupinesPositioning AttributePostdoctoral FellowProductivityPrognosisPropertyRadiationRadiation therapyRadiation-Sensitizing AgentsRadiosensitizationResearchResistanceResourcesRoleSecureShapesStimulation of Cell ProliferationTestingTherapeuticTrainingTranslatingTranslationsWNT Signaling PathwayWorkcancer cellcancer heterogeneitycancer stem cellcancer typecell typechemotherapyconventional therapydisorder controlexperiencegraduate studentimmune activationimprovedinhibitorinsightinterestmembernovel therapeutic interventionpalmitoylationpancreatic cancer cellspancreatic cancer modelpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpancreatic neoplasmpharmacologicprofessorprogramsradiation resistanceresponseself-renewalsmall moleculestemstem-like cellstemnesstargeted treatmenttenure tracktherapeutic evaluationtherapeutic targettherapy resistanttranscriptomicstreatment responsetreatment strategytumortumor growthtumor heterogeneitytumor microenvironment
项目摘要
PROJECT SUMMARY/ABSTRACT
Individual cells within a given cancer type are capable of expressing a diversity of phenotypic states resulting
from an underlying heterogeneity of genetic, epigenetic, transcriptomic, and molecular features. How this
diversity evolves and influences therapeutic response is an essential question in cancer biology. One emerging
mechanism of developing such heterogeneity is the evolution of microenvironmental niches within tumors that
support a cancer stem cell (CSC) state. CSCs are defined by their functional capabilities such as long-term self-
renewal, the capacity to give rise to a range of differentiated cell types, and enhanced tumor-forming ability.
They are also believed to drive resistance to anti-tumor therapies, such as radiation therapy. Pancreatic ductal
adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year overall survival of <10% and a dire need for novel
therapeutic strategies. Radiation is an integral part of PDAC therapy, however not all cancer cells respond.
Identifying mechanisms of radioresistance would transform the clinical management of PDAC. Using pancreatic
tumor models, our preliminary results suggest that secreted Wnt ligands produced by one cancer cell subset
drive a Lgr5+ stem-like state in another cancer cell subset, in essence forming a supportive niche that promotes
stemness within pancreatic tumors. In this proposal, I will test the central hypothesis that Wnt-driven cellular
phenotypic heterogeneity and stemness promote radiotherapy resistance in pancreatic adenocarcinoma. I will
examine the role of pancreatic tumor cell subpopulations in radiation resistance, including the Lgr5+ cells (Aim
1) and the Wnt producing niche (Aim 2). Under Aim 1, I will characterize the cancer stem cell properties of
Lgr5+ cells in pancreatic cancer, their relative resistance to radiation therapy, and their role in tumor
repopulation. These results will determine whether Lgr5+ cells are CSCs and drivers of radioresistance in
established tumors and inform their molecular characteristics, which may provide added means to target these
cells. Under Aim 2, I will investigate the targeting of the Wnt-producing niche in combination with radiation.
Specifically, I will use genetic or pharmacologic perturbation of the Wnt pathway in combination with radiation
and assay tumor response and animal survival. These efforts will test the therapeutic potential of Wnt inhibitors
as radiosensitizers in PDAC. Collectively, this work will facilitate basic mechanistic insights into both cellular
heterogeneity and radioresistance, with the ultimate goal of translating these discoveries and developing
improved treatment strategies for PDAC patients.
项目总结/摘要
给定癌症类型中的单个细胞能够表达多种表型状态,从而
遗传、表观遗传、转录组和分子特征的潜在异质性。这如何
多样性演变和影响治疗反应是癌症生物学中的基本问题。一种新兴
发展这种异质性的机制是肿瘤内微环境生态位的演变,
支持癌症干细胞(CSC)状态。CSC由其功能性能力定义,例如长期自我管理能力。
更新,产生一系列分化细胞类型的能力,以及增强的肿瘤形成能力。
它们也被认为会导致抗肿瘤治疗的耐药性,如放射治疗。胰腺导管
腺癌(PDAC)预后不佳,5年总生存率<10%,迫切需要新的治疗方法。
治疗策略放射是PDAC治疗的一个组成部分,但并非所有癌细胞都有反应。
确定放射抗性的机制将改变PDAC的临床管理。使用胰腺
在肿瘤模型中,我们的初步结果表明,一种癌细胞亚群分泌的Wnt配体
在另一个癌细胞亚群中驱动Lgr 5+干细胞样状态,本质上形成一个支持性的小生境,
胰腺肿瘤内的干性。在这个建议中,我将测试中心假设,即Wnt驱动的细胞
表型异质性和干性促进胰腺癌的放射治疗抵抗。我会
检查胰腺肿瘤细胞亚群在放射抗性中的作用,包括Lgr 5+细胞(Aim
1)和Wnt生产生态位(Aim 2)。在目标1下,我将描述以下癌症干细胞的特性:
胰腺癌中的LGR 5+细胞、它们对放射治疗的相对抵抗性及其在肿瘤中的作用
再繁殖这些结果将确定Lgr 5+细胞是否是CSC和辐射抗性的驱动因素。
建立的肿瘤,并告知他们的分子特征,这可能提供额外的手段,以针对这些
细胞在目标2下,我将研究结合辐射的Wnt产生生态位的靶向。
具体来说,我将使用Wnt途径的遗传或药理学干扰与辐射相结合
并测定肿瘤反应和动物存活率。这些努力将测试Wnt抑制剂的治疗潜力
作为PDAC中的放射增敏剂。总的来说,这项工作将促进对细胞和细胞生物学的基本机械见解。
异质性和辐射抗性,最终目标是转化这些发现,
改善PDAC患者的治疗策略。
项目成果
期刊论文数量(1)
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 Comparison of Pancreatic Ductal Adenocarcinoma Models Identifies a Conserved Highly Plastic Basal Cell State.
- DOI:10.1158/0008-5472.can-22-1742
- 发表时间:2022-10-04
- 期刊:
- 影响因子:11.2
- 作者:
- 通讯作者:
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Kenneth L Pitter其他文献
Kenneth L Pitter的其他文献
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{{ truncateString('Kenneth L Pitter', 18)}}的其他基金
Cellular phenotypic heterogeneity and resistance to radiotherapy in pancreatic adenocarcinoma
胰腺腺癌的细胞表型异质性和放疗耐药性
- 批准号:
10254822 - 财政年份:2021
- 资助金额:
$ 39.38万 - 项目类别:
Characterizing the functional stem-like properties of primary and recurrent gliom
表征原发性和复发性神经胶质细胞的功能性干细胞特性
- 批准号:
8201592 - 财政年份:2011
- 资助金额:
$ 39.38万 - 项目类别:
Characterizing the functional stem-like properties of primary and recurrent gliom
表征原发性和复发性神经胶质细胞的功能性干细胞特性
- 批准号:
8490491 - 财政年份:2011
- 资助金额:
$ 39.38万 - 项目类别:
Characterizing the functional stem-like properties of primary and recurrent gliom
表征原发性和复发性神经胶质细胞的功能性干细胞特性
- 批准号:
8535229 - 财政年份:2011
- 资助金额:
$ 39.38万 - 项目类别:
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