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

项目摘要 癌细胞、细胞外基质（ECM）和癌相关成纤维细胞（CAFs）是三个关键的 导致结直肠癌和鳞状细胞癌肿瘤进展的因素 癌症类型。CAF通常与恶性肿瘤的发展有关 因为CAFs分泌促进转移的细胞因子和异常的存款胶原蛋白，促进整合素- 依赖性肿瘤侵袭，并形成抗癌药物递送的障碍。尽管有详细的研究 关于CAFs在肿瘤进展中的作用，基质细胞成为CAFs的机制仍然不清楚。 清除：在癌症的早期阶段，基质中的正常成纤维细胞如何转化为CAFs？在这个项目中，我 将测试癌细胞通过机械重组细胞外基质来促进CAF诱导的假设。 基质，从而打破CAF诱导因子的扩散屏障。共培养系统，其包含 结直肠癌球体和多种类型的基质细胞作为测试平台将被构建， 初步测试。如果被证明是有效的，我将使用我的假设来开发新的治疗方法， 重塑被抑制以降低结肠直肠癌中肿瘤进展的速率。两个治疗 将测试以下策略：（1）在肿瘤微环境中直接应用ECM交联剂;（2） 植入分泌ECM交联酶和其他抗癌药物的基因工程成纤维细胞 生物分子结肠直肠癌小鼠模型将用于评估新治疗的疗效。

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.