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

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。

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.