Tumor organoids: applications in cancer modeling and potentials in precision medicine

Abstract

Cancer is a top-ranked life-threatening disease with intratumor heterogeneity. Tumor heterogeneity is associated with metastasis, relapse, and therapy resistance. These factors contribute to treatment failure and an unfavorable prognosis. Personalized tumor models faithfully capturing the tumor heterogeneity of individual patients are urgently needed for precision medicine. Advances in stem cell culture have given rise to powerful organoid technology for the generation of in vitro three-dimensional tissues that have been shown to more accurately recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. Tumoroids in vitro serve as an important component of the pipeline for the discovery of potential therapeutic targets and the identification of novel compounds. In this review, we will summarize recent advances in tumoroid cultures as an excellent tool for accurate cancer modeling. Additionally, vascularization and immune microenvironment modeling based on organoid technology will also be described. Furthermore, we will summarize the great potential of tumor organoids in predicting the therapeutic response, investigating resistance-related mechanisms, optimizing treatment strategies, and exploring potential therapies. In addition, the bottlenecks and challenges of current tumoroids will also be discussed in this review.

Keywords: Cancer; Drug discovery; Organoid; Patient-derived xenografts; Therapy response prediction; Tumor microenvironment.

Fig. 1

Main steps of PDO generation and main applications of PDOs. Human cancer tissues containing cancer cells, adult stem cells, pluripotent stem cells, or cancer stem cells are occasionally first disassociated into very small pieces, cell clusters, or single cells using mechanical and chemical methods and cultured under proper 3D conditions in hydrogels with ECM components (A). Tumoroids mimic the primary tissues in terms of histopathological features, genetic profiles, mutational landscape, and even responses to therapy, and tumoroid biobanks can be established (B). 3D, three-dimensional; ECM, extracellular matrix; PDO, patient-derived organoid

Fig. 2

Workflow of organoid vascularization. Implantation of tumoroids into highly vascularized tissues in animals is an effective approach for organoid vascularization. After organoids are engrafted in vasculature-rich mouse tissue, the host vasculature infiltrates the organoids. Another approach to generate vascularized organoids is combining the coculture of mixed cells or microfluidic platforms

Fig. 3

Modeling the immune microenvironment in a coculture system of tumoroids and immune cells. Two approaches have been developed to coculturing organoids and immune cells: maintenance and expansion of native immune cells in tumoroids and addition of immune cells to organoid culture. Immune cells can be obtained from the ALI culture system. Tumoroids are embedded in a collagen gel with one side exposed to air and the other side in contact with the liquid culture medium. Cocultures of tumoroids and immune cells may promote the prediction and evaluation of individual tumor responses to clinically used immunotherapies