A 3D bioprinted liposarcoma tumor microenvironment model recapitulates stroma-driven invasion and chemoresistance

Abstract

Liposarcoma is a challenging soft tissue sarcoma where the tumor microenvironment (TME) critically drives progression, invasion, and therapy resistance. Conventional preclinical models, particularly 2D cultures, fail to recapitulate this complex interplay, hindering the development of effective therapies. To address this, we developed and validated a novel 3D bioprinted liposarcoma model that integrates human liposarcoma cells, cancer-associated fibroblasts (CAFs), and human umbilical vein endothelial cells within a biomimetic collagen/hyaluronic acid composite hydrogel. This engineered TME model successfully reproduced key in vivo features, including a soft tissue mechanical environment, CAF activation, and angiogenic network formation. Compared to 2D or 3D mono-cultures, the complete TME significantly promoted liposarcoma cell proliferation and invasion. Transcriptomic analysis revealed that the TME induces profound functional reprogramming. Liposarcoma cells were driven toward an aggressive, epithelial–mesenchymal transition like phenotype via activation of TGF-β and other hallmark cancer pathways, while CAFs were activated into a pro-inflammatory, highly proliferative state. Critically, the 3D TME model conferred significant resistance to the standard chemotherapeutic agent, doxorubicin, which confirmed that this chemoresistance is mediated by a combination of physical barriers arising from cell–matrix remodeling and protective paracrine signaling from the stromal cells. In conclusion, our 3D bioprinted TME model provides a physiologically relevant and robust preclinical platform. It serves as a powerful tool for investigating the molecular mechanisms of TME-driven liposarcoma progression and chemoresistance, offering a new paradigm for the high-throughput screening of novel therapeutics that target tumor–stroma interactions.