Tumors comprised a tightly surrounded tumor microenvironment, made up of non-cellular extracellular matrix (ECM) and stromal cells. Although treatment response is often attributed to tumor heterogeneity, progression and malignancy are profoundly influenced by tumor cell interactions with the surrounding ECM. Here, we used a tumor organoid model, consisting of hepatic stellate cells (HSCs) embedded in collagen type 1 (Col1) and colorectal cancer cell (HCT-116) spheroids, to determine the relationship between the ECM architecture, cancer cell malignancy, and chemoresistance. Exogenous transforming growth factor beta (TGF-β) used to activate the HSCs increased the remodeling and bundling of Col1 in the ECM around the cancer spheroid. A dense ECM architecture inhibited tumor cell growth, reversed their mesenchymal phenotype, preserved stem cell population, and reduced chemotherapy response. Overall, our results demonstrate that controlled biofabrication and manipulation of the ECM in tumor organoids results enables studying tumor cell-ECM interactions and better understand tumor cell response to chemotherapies.

肿瘤由紧密包围的肿瘤微环境组成，由非细胞的细胞外基质（ECM）和基质细胞组成。尽管治疗反应通常归因于肿瘤异质性，但肿瘤细胞与周围 ECM 的相互作用对进展和恶性程度产生深远影响。在这里，我们使用了一个肿瘤类器官模型，该模型由嵌入 1 型胶原蛋白 (Col1) 和结直肠癌细胞 (HCT-116) 球体中的肝星状细胞 (HSC) 组成，以确定 ECM 结构、癌细胞恶性肿瘤和肿瘤细胞之间的关系。化学耐药性。用于激活 HSC 的外源转化生长因子 β (TGF-β) 增加了癌球体周围 ECM 中 Col1 的重塑和捆绑。致密的 ECM 结构抑制肿瘤细胞生长，逆转其间充质表型，保留干细胞群，并降低化疗反应。总的来说，我们的结果表明，在肿瘤类器官中对 ECM 进行受控生物制造和操作，能够研究肿瘤细胞-ECM 相互作用，并更好地了解肿瘤细胞对化疗的反应。