Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin

Simple Summary The pathogenesis of osteosarcoma relies on complex interactions between developing cancer and surrounding tissue, which includes proteins of the extracellular matrix. Mapping ECM-cell interactions and ECM composition is highly important to understand and predict cancer response to chemotherapy and potentially give rise to alternative targets for therapy. Our study aims at generating a 3D model that recapitulates interactions of cancer cells with ECM components and with non-tumor stromal cells and at elucidating the role of ECM deposition in chemotherapy response. Dissecting the contribution of the tumor environment and the role of collagenic and non-collagenic proteins of the ECM will provide additional knowledge for the development of new antitumor strategies. The extracellular matrix (ECM) modulates cell behavior, shape, and viability as well as mechanical properties. In recent years, ECM disregulation and aberrant remodeling has gained considerable attention in cancer targeting and prevention since it may stimulate tumorigenesis and metastasis. Here, we developed an in vitro model that aims at mimicking the in vivo tumor microenvironment by recapitulating the interactions between osteosarcoma (OS) cells and ECM with respect to cancer progression. We long-term cultured 3D OS spheroids made of metastatic or non-metastatic OS cells mixed with mesenchymal stromal cells (MSCs); confirmed the deposition of ECM proteins such as Type I collagen, Type III collagen, and fibronectin by the stromal component at the interface between tumor cells and MSCs; and found that ECM secretion is inhibited by a neutralizing anti-IL-6 antibody, suggesting a new role of this cytokine in OS ECM deposition. Most importantly, we showed that the cytotoxic effect of doxorubicin is reduced by the presence of Type I collagen. We thus conclude that ECM protein deposition is crucial for modelling and studying drug response. Our results also suggest that targeting ECM proteins might improve the outcome of a subset of chemoresistant tumors.