Bioprinted Gastric Cancer Platform with Tumor Vasculature for Implementing Precision Personalized Medicine Targeted Towards Gastric Cancer

Abstract

The progression of gastric cancer cells is significantly influenced by the tumor microenvironment's physiologically relevant conditions. Accurate prediction of treatment response is crucial due to the inherent therapeutic resistance arising from genetic diversity, varying tumor growth rates, and the intricate tumor milieu. To address this, our study combined the benefits of biomaterials engineering and a patient-centric approach. Using three-dimensional (3D) cell printing, we established a gastric cancer model with gastric tissue-specific bioinks to emulate the biophysical and biochemical features of the gastric cancer environment. We innovatively developed a decellularization process for stomach tissue-derived decellularized extracellular matrix (st-dECM) bioink, evaluating its potential in enhancing the aggressiveness of gastric cancer cells through both histological and genetic methodologies. The incorporation of enhancing stiffness of st-dECM bioink was pivotal in optimizing the matrix's mechanical properties, leading to the advancement of gastric cancer progression, a unique feature promoting in vitro gastric cancer model development. Additionally, this enhanced st-dECM bioink facilitated the 3D printing of various self-supporting structures, including gastric rugae. In tandem, we introduced a vascularized organoid model (VOM) that includes patient-derived gastric cancer organoids (PDOs), a perfusable and functional endothelium, and st-dECM bioink. This model proved instrumental in predicting clinical responses to VEGFR2-targeted therapies among gastric cancer patients, revealing a correlation between VOM outcomes and specific PDO molecular subtypes. Importantly, VOMs effectively mirrored the clinical outcomes observed in patients undergoing VEGFR2 inhibitor treatment. Collectively, our integrated approach underscores the potential of using a physiologically relevant gastric cancer system combined with a VOM for advancing preclinical trials, guiding personalized testing, and facilitating therapeutic drug discovery, particularly for cancers that lack standardized treatment protocols.