A personalized colorectal cancer-on-a-chip for assessing tumor-microbiome crosstalk
用于评估肿瘤微生物串扰的个性化结直肠癌芯片
基本信息
- 批准号:9912739
- 负责人:
- 金额:$ 16.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdherenceAnimalsAntineoplastic AgentsAsiansBacteriaBiological MarkersBiomechanicsBiopsyBlood VesselsBlood capillariesCancer EtiologyCancer ModelCarcinomaCessation of lifeCharacteristicsCoculture TechniquesColonColorectal CancerComplexCustomDNA Sequence AlterationDefecationDevelopmentDiagnosticEcosystemEpithelialEpitheliumEthnic OriginEthnic groupEtiologyFemaleFunctional disorderFusobacterium nucleatumGal-GalNAcGeneticGenetic HeterogeneityGenetic VariationGoalsHeterogeneityHispanicsHumanImpairmentIn VitroIndividualKnowledgeLamina PropriaMechanicsMetastatic Neoplasm to the LiverMicrofluidic MicrochipsModelingMolecularMucous MembraneNeoplasm MetastasisOrganOrganoidsPatientsPeristalsisPopulationPrecision Medicine InitiativeProductionProteinsRaceReactive Oxygen SpeciesRoleSamplingSeminalSex DifferencesSpecificitySubmucosaSurfaceSystemTherapeuticTherapeutic InterventionTissuesToxinTreatment-related toxicityValidationVisualizationanti-cancer therapeuticanticancer researchantitumor effectbasecancer immunotherapycancer typecohortcolon cancer patientscolorectal cancer screeningconditioningdesigndrug metabolismdysbiosisfecal microbiomefecal transplantationgender differencegenotoxicitygut microbiomehost microbiomeimprovedin vivoindividual patientinnovationinsightmalemicrobialmicrobiomemicrosystemsnovelpathobiontpublic health relevancereconstitutionresponsesexspatiotemporaltumortumor growthtumor metabolismtumor microbiometumorigenesistumorigenic
项目摘要
Colorectal cancer (CRC) is one of the leading causes of cancer death. Quantitative assessment of host-gut
microbiome crosstalk is important in CRC researches because impaired microbial population (dysbiosis)
dominated by detrimental pathobionts such as Fusobacterium nucleatum often leads to the initiation of CRC
(tumorigenesis) in genetically susceptible individuals. Development of a patient-specific tumor-microbiome
model is also important because microbial signature in the colon is a potent identifier for CRC screening,
suggesting the diagnostic and therapeutic potential. However, current CRC models are challenged to reflect
heterogeneous genetic mutations, microbial dysbiosis, and robust co-culture necessary to demonstrate tumor-
microbiome crosstalk. Developing a modular patient-specific CRC model that can quantitatively assess
molecular and cellular characteristics of tumor-microbiome crosstalk germane to CRC is a critical unmet need.
The overall goal is to develop a pathomimetic, patient-specific colorectal cancer-on-a-chip (CRC Chip) to
quantitatively assess host-microbiome interactions germane to CRC pathophysiology and tumorigenesis. Our
design strategy is to improve the current in vitro culture models by integrating gut-on-a-chip microsystem and
biopsy-derived, three-dimensional (3D) colon organoid (colonoid) culture. The lumen-lamina propria (LP)-
capillary tissue interface will enable to recreate an anoxic-oxic gradient at steady-state in the lumen-vascular
layers. We will quantitatively visualize tumorigenic intercellular crosstalk under peristalsis-like dynamics. We aim
to build “in vitro cohort avatars” from CRC patient cohorts with four race/ethnicities and the gender difference.
Once the system is fully developed, co-culture with living CRC microbiome on the 3D colonic mucosa for two
weeks will allow the longitudinal assessment of tumor-microbiome crosstalks germane to tumorigenesis. We
envision that the CRC Chip is a compelling platform to advance knowledge in cancer researches because it can
customize the transformative potential towards the anticipated long-term applications. The successful
development of a CRC Chip with accomplished quantitative milestones will enable to study the role of intra-tumor
bacteria on the metabolism of cancer drugs, contribution of gut microbiome on the efficacy of cancer
immunotherapy, anti-tumor effect of microbiome, validation of microbial contribution to the trigger of metastasis,
and validation of a novel anti-tumor strategy such as fecal microbiota transplantation (FMT). Our CRC Chip will
potentiate to define the patient-specific anti-cancer therapeutics by reflecting patient’s microbiome signature and
heterogeneous genetic variations and decipher the salient role of gut microbiome on the initiation and control of
CRC.
结直肠癌(CRC)是癌症死亡的主要原因之一。宿主肠道定量评价
微生物组串扰在CRC研究中很重要,因为受损的微生物种群(生态失调)
由有害的致病生物如具核梭杆菌(Fusobacteriumnucleatum)主导的大肠杆菌感染常常导致CRC的发生
(肿瘤发生)在遗传易感个体。开发患者特异性肿瘤微生物组
模型也很重要,因为结肠中的微生物特征是CRC筛查的有效标识符,
显示了诊断和治疗的潜力。然而,目前的CRC模型面临的挑战是,
异质性基因突变,微生物生态失调,和强大的共培养,以证明肿瘤-
微生物组串扰开发一个模块化的患者特异性CRC模型,
与CRC密切相关的肿瘤-微生物组串扰的分子和细胞特征是一个关键的未满足的需求。
总体目标是开发一种拟病理的、患者特异性的结肠直肠癌芯片(CRC芯片),
定量评估与CRC病理生理学和肿瘤发生密切相关的宿主-微生物组相互作用。我们
设计策略是通过集成gut-on-a-chip微系统和
活组织检查衍生的三维(3D)结肠类器官(类结肠)培养。腔-固有层(LP)-
毛细血管组织界面将能够在管腔-血管内重建处于稳态的缺氧-有氧梯度
层次。我们将定量可视化肿瘤样动力学下的致瘤细胞间串扰。我们的目标
从具有四个人种/种族和性别差异的CRC患者队列构建“体外队列化身”。
一旦系统完全开发,与3D结肠粘膜上的活CRC微生物组共培养两个月。
几周的时间将允许对与肿瘤发生密切相关的肿瘤-微生物组串扰进行纵向评估。我们
我认为CRC芯片是一个引人注目的平台,可以促进癌症研究的知识,因为它可以
为预期的长期应用定制变革潜力。成功
具有已完成的定量里程碑的CRC芯片的开发将能够研究肿瘤内
细菌对癌症药物代谢的影响,肠道微生物组对癌症疗效的贡献
免疫疗法,微生物组的抗肿瘤作用,微生物对转移触发的贡献的验证,
以及验证一种新的抗肿瘤策略,如粪便微生物群移植(FMT)。我们的CRC芯片
- 通过反映患者的微生物组特征,有可能定义患者特异性抗癌治疗剂,
异质性遗传变异,并破译肠道微生物组在启动和控制
《儿童权利公约》。
项目成果
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