A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery
A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery
批准号:
10337608
负责人:
Gary D Luker
金额:
$5.92万
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
项目状态:
已结题
起止时间:
2019-06-01 至 2024-05-31
关键词:
3-DimensionalAddressAntineoplastic AgentsBreast Cancer cell lineCarcinomaCellsDisease modelDropsEngineeringExtracellular MatrixFibroblastsGrowthHumanImmersionModelingNeoplasm MetastasisOutcomePatient-Focused OutcomesPatientsPhasePhysiologicalPolymersPropertyProteinsResearchRoboticsSignal TransductionStromal CellsStromal NeoplasmSystemTechnologyTissuesaqueousbasecancer cellcancer drug resistancedrug developmentdrug discoverydrug sensitivitydrug testingeffective therapyflexibilityimproved outcomein vivomalignant breast neoplasmtriple-negative invasive breast carcinomatumortumor growth
中文摘要
项目摘要
肿瘤间质,包括细胞外基质(ECM)和细胞,基本上调节肿瘤的所有方面。
肿瘤生长和转移。肿瘤中癌细胞、基质细胞和ECM之间的信号传导促进
癌细胞增殖和耐药性等关键结果。因此,破坏基质-
癌细胞信号传导对于恢复癌细胞的药物敏感性和改善治疗结果至关重要。
患者尽管认识到了这一点,但缺乏生理性的、高通量的人类肿瘤模型,
阻碍了靶向肿瘤-基质相互作用的药物开发和发现工作。
我们将通过开发高通量肿瘤微组织技术来重建肿瘤微组织来满足这一需求
本发明的目的在于降低天然肿瘤的复杂性,并使针对肿瘤基质信号传导的药物测试成为可能。这项简单的技术
是基于两步机器人微图案化的用户定义的癌细胞,基质细胞,和ECM使用
微孔板中的聚合物含水两相系统。癌细胞的3D质量在水性溶液中形成。
纳米滴沉降在微孔的底部并且与浸没水相不混溶。第二
然后分配含有基质组分的水性液滴以与纳米液滴合并
癌细胞团在孵育后自发产生微组织。这种方法独特地提供了
结合组织特异性基质蛋白和不同基质细胞的灵活性,
肿瘤在体内的物理化学性质。我们将使用三阴性乳腺癌来验证这项技术,
癌症(TNBC)作为疾病模型,证明癌相关成纤维细胞(CAF)和
ECM对癌细胞增殖和基质侵袭的影响。这些研究将使用工程肿瘤模型,
TNBC细胞系和患者来源的CAF,以建立定制我们的肿瘤模型的可行性,
患者特异性细胞。通过这项研究,我们希望建立我们的肿瘤模型,作为一个变革性的
这一进展将广泛用于乳腺癌的药物发现和机制研究。
英文摘要
Project Summary
Tumor stroma, encompassing both extracellular matrix (ECM) and cells, regulates essentially all aspects of
tumor growth and metastasis. Signaling among cancer cells, stromal cells, and ECM in tumors promotes
proliferation of cancer cells and drug resistance among other key outcomes. Therefore, disrupting stroma-
cancer cells signaling is essential to restoring drug sensitivity of cancer cells and improving outcomes for
patients. Despite this recognition, the lack of physiologic, high throughput human tumors models significantly
impedes drug development and discovery efforts targeting tumor-stromal interactions.
We will address this need by developing a high throughput tumor microtissue technology to recreate the
complexity of native tumors and enable drug testing against tumor-stromal signaling. This facile technology
is based on two-step robotic micropatterning of user-defined cancer cells, stromal cells, and ECM using a
polymeric aqueous two-phase system in microwell plates. A 3D mass of cancer cells is formed in an aqueous
nanodrop settled at the bottom of a microwell and immiscible from the immersion aqueous phase. A second
aqueous drop containing the stromal components is then dispensed to merge with the nanodrop and surround
the cancer cell mass to spontaneously generate a microtissue upon incubation. This approach uniquely offers
the flexibility of incorporating tissue-specific matrix proteins and different stromal cells to reproduce
physicochemical properties of tumors in vivo. We will validate this technology using triple negative breast
cancer (TNBC) as a disease model, demonstrating effects of carcinoma-associated fibroblasts (CAFs) and
ECM on proliferation and matrix invasion of cancer cells. These studies will use engineered tumor models of
both TNBC cell lines and patient-derived CAFs to establish the feasibility of tailoring our tumor model to
patient-specific cells. Through this research, we expect to establish our tumor model as a transformative
advance that will be implemented broadly for drug discovery and mechanistic studies of breast cancer.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
Integrated Imaging Tools for Intercellular Chemokine Signalling
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批准号:10706896
-
项目类别:
-
资助金额:$21.88万
-
财政年份:2023
-
负责人:Gary D Luker
-
依托单位:
Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis
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批准号:10360496
-
项目类别:
-
资助金额:$60.82万
-
财政年份:2019
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负责人:Gary D Luker
-
依托单位:
Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis
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批准号:9891988
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项目类别:
-
资助金额:$62.07万
-
财政年份:2019
-
负责人:Gary D Luker
-
依托单位:
Imaging Disease Heterogeneity and Response to Therapy in Myelofibrosis
-
批准号:10563197
-
项目类别:
-
资助金额:$60.82万
-
财政年份:2019
-
负责人:Gary D Luker
-
依托单位:
A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery
-
批准号:10161750
-
项目类别:
-
资助金额:$36.5万
-
财政年份:2019
-
负责人:Gary D Luker
-
依托单位:
A High Throughput Human Tumor Modeling Technology for Cancer Drug Discovery
-
批准号:10330116
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项目类别:
-
资助金额:$16.64万
-
财政年份:2019
-
负责人:Gary D Luker
-
依托单位:
A Novel High Throughput Tumor Spheroid Microtechnology
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批准号:8625056
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项目类别:
-
资助金额:$25.75万
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财政年份:2013
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负责人:Gary D Luker
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依托单位:
A Novel High Throughput Tumor Spheroid Microtechnology
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批准号:8738627
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项目类别:
-
资助金额:$24.57万
-
财政年份:2013
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负责人:Gary D Luker
-
依托单位:
Modeling Therapy of Disseminated Cancer Cells in Bone Marrow (PQ 17)
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批准号:8704735
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项目类别:
-
资助金额:$31.8万
-
财政年份:2012
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负责人:Gary D Luker
-
依托单位:
Modeling Therapy of Disseminated Cancer Cells in Bone Marrow (PQ 17)
-
批准号:8532861
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项目类别:
-
资助金额:$34.09万
-
财政年份:2012
-
负责人:Gary D Luker
-
依托单位:
Modeling Therapy of Disseminated Cancer Cells in Bone Marrow (PQ 17)
-
批准号:8374192
-
项目类别:
-
资助金额:$37.86万
-
财政年份:2012
-
负责人:Gary D Luker
-
依托单位:
Olympus FV1000-MPE Confocal & Multi-Photon Imaging System
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批准号:7834613
-
项目类别:
-
资助金额:$93.96万
-
财政年份:2010
-
负责人:Gary D Luker
-
依托单位:
Microfluidic Models of Metastatic Cancer
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批准号:8015364
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项目类别:
-
资助金额:$30.22万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Molecular Imaging of Chemokine Receptor Signaling
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批准号:8204602
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项目类别:
-
资助金额:$30.24万
-
财政年份:2009
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负责人:Gary D Luker
-
依托单位:
Microfluidic Models of Metastatic Cancer
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批准号:8215885
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项目类别:
-
资助金额:$30.41万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Molecular Imaging of Chemokine Receptor Signaling
-
批准号:8387781
-
项目类别:
-
资助金额:$28.4万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Molecular Imaging of Chemokine Receptor Signaling
-
批准号:7563656
-
项目类别:
-
资助金额:$31.25万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Molecular Imaging of Chemokine Receptor Signaling
-
批准号:7991369
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项目类别:
-
资助金额:$30.26万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Microfluidic Models of Metastatic Cancer
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批准号:8458895
-
项目类别:
-
资助金额:$28.55万
-
财政年份:2009
-
负责人:Gary D Luker
-
依托单位:
Microfluidic Models of Metastatic Cancer
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批准号:7649893
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项目类别:
-
资助金额:$31.24万
-
财政年份:2009
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负责人:Gary D Luker
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依托单位:
海外基金