Sporadic cell death in macroscale 3D tumor grafts with high drug resistance by activating cell-ECM interactions

In the tumor microenvironment (TME), the extracellular matrix (ECM) provides a dynamic structure for cell adhesion and cancer cell motility, such as migration and invasion, as well as remodeling. Matrix metalloproteinases (MMPs) promote cancer cell motility, which contributes to inducing drug resistance and thereby acquiring aggressive features. The drug resistance-induced 3Din vitrotumor model can be an effective model for therapeutic strategies for anticancer drugs targeting aggressive cancer cells. Here, we describe highly drug-resistant multicellular tumoroids (MCTs)-ECM tumor grafts under a macroscale dense 3Din vitromodel through a combination of numerous MCTs and a collagen matrix. MCTs-ECM tumor grafts promote the high activity of MMP2 and MMP9 compared to general MCTs and induced cancer cell motility. Then, after the administration of anticancer drugs, the tumor grafts show increased drug resistance, with both the sporadic distribution of necrotic cells and the reduction of apoptotic portions, by activating cancer cell motility. MCTs-ECM tumor graft could be useful as a macroscale tumor graft model for inducing drug resistance by activating cancer cell motility and evaluating the efficacy of anticancer drugs targeting cancer with aggressive features.