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Engineered Fibroblasts as Cell Therapy to Treat Colorectal Cancer via Tumor Stroma Stabilization

工程成纤维细胞作为细胞疗法通过肿瘤基质稳定治疗结直肠癌

基本信息

批准号：
10226326
负责人：
Wei-Hung Jung
金额：
$ 4.6万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-08-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226326
关键词：
3-Dimensional Affect Antineoplastic Agents Architecture Autologous Transplantation Biochemical Cancer Etiology Cancer Model Carcinoma Cell Therapy Cessation of life Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Coin Collagen Colon Colorectal Cancer Colorectal Neoplasms Cross-Linking Reagents Deposition Dermal Development Diffusion Doctor of Philosophy Drops Drug Delivery Systems Early Diagnosis Engineering Enzymes Etiology Extracellular Matrix Fibroblasts Genes Genetic Engineering Genome Health Implant In Vitro Integrins Lead Length Link Malignant Neoplasms Malignant neoplasm of ovary Mechanics Mediating Mus Neoplasm Metastasis Pathologic Pathway interactions Pattern Phenotype Play Proteomics Research Research Project Grants Role Signal Pathway Squamous cell carcinoma Stromal Cells Survival Rate System Testing Therapeutic Therapeutic Effect Time Tissues Training Transglutaminases Translating Transportation Treatment Efficacy Woman anti-cancer biophysical properties cancer cell cancer type clinical application colorectal cancer treatment crosslink cytokine effective therapy efficacy evaluation efficacy testing exosome extracellular vesicles genipin improved improved outcome in vivo malignant breast neoplasm mechanical force men metastatic colorectal mouse model promoter screening therapeutic evaluation trait treatment strategy tumor tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Cancer cells, extracellular matrix (ECM) and carcinoma-associated fibroblasts (CAFs) are three critical factors contributing to tumor progression in colorectal cancer and squamous cell carcinoma, among other cancer types. CAFs are often associated with the development of high-grade malignancies of poor prognoses because CAFs secrete metastasis-promoting cytokines and abnormally deposit collagen, facilitating integrin- dependent cancer invasion and forming hindrance of anti-cancer drug delivery. Despite the detailed studies about the role of CAFs in tumor progression, the mechanism by which stromal cells become CAFs is still not clear: how normal fibroblasts in stroma are transformed to CAFs during early stages of cancer? In this project, I will test the hypothesis that cancer cells facilitate CAF induction by mechanically reorganizing extracellular matrix and thus breaking down the diffusion barrier of CAF-inducing factors. A coculture system containing colorectal cancer spheroids and multiple types of stromal cells as the testing platform will be constructed for the preliminary tests. If proven valid, I will use my hypothesis to develop new treatments where ECM remodeling is suppressed to decrease the rate of tumor progression in colorectal cancer. Two treatment strategies will be tested: (1) direct applying ECM crosslinking agents in the tumor microenvironment; (2) implanting genetically engineered fibroblasts secreting ECM crosslinking enzymes and other anti-cancer biomolecules. Colorectal cancer mouse models will be used to evaluate the efficacy of the new treatments.

项目总结癌细胞、细胞外基质(ECM)和肿瘤相关成纤维细胞(CAF)是三个关键的结直肠癌和鳞状细胞癌的肿瘤进展因素等癌症类型。CAF通常与预后不良的高级别恶性肿瘤的发展有关。由于CAF分泌促进转移的细胞因子，并异常沉积胶原，促进整合素- 依赖肿瘤侵袭，形成抗癌药物输送障碍。尽管进行了详细的研究关于CAF在肿瘤进展中的作用，基质细胞成为CAF的机制尚不清楚清晰：在癌症早期，间质中的正常成纤维细胞是如何转化为CAF的？在这个项目中，我将检验这样一种假设，即癌细胞通过机械重组细胞外来促进CAF的诱导从而打破CAF诱导因子的扩散障碍。包含以下内容的共文化体系将构建结直肠癌球体和多种间质细胞作为检测平台初步测试。如果证明有效，我将使用我的假设来开发新的治疗方法，其中ECM 抑制重塑以降低结直肠癌的肿瘤进展速度。两种疗法将测试的策略：(1)在肿瘤微环境中直接应用细胞外基质交联剂；(2) 将分泌细胞外基质交联酶和其他抗癌物质的基因工程成纤维细胞植入体内生物分子。结直肠癌小鼠模型将被用来评估新疗法的疗效。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stretching DNA origami: effect of nicks and Holliday junctions on the axial stiffness.

DOI：
10.1093/nar/gkaa985
发表时间：
2020-12-02
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Jung WH;Chen E;Veneziano R;Gaitanaros S;Chen Y
通讯作者：
Chen Y

Membrane Ruffling is a Mechanosensor of Extracellular Fluid Viscosity.

DOI：
10.1038/s41567-022-01676-y
发表时间：
2022-09
期刊：
Nature physics
影响因子：
19.6
作者：
通讯作者：

A novel human endometrial epithelial cell line for modeling gynecological diseases and for drug screening.

DOI：
10.1038/s41374-021-00624-3
发表时间：
2021-11
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
0
作者：
Park Y;Jung JG;Yu ZC;Asaka R;Shen W;Wang Y;Jung WH;Tomaszewski A;Shimberg G;Chen Y;Parimi V;Gaillard S;Shih IM;Wang TL
通讯作者：
Wang TL