Tumor organoids: synergistic applications, current challenges, and future prospects in cancer therapy

Abstract

Patient-derived cancer cells (PDCs) and patient-derived xenografts (PDXs) are often used as tumor models, but have many shortcomings. PDCs not only lack diversity in terms of cell type, spatial organization, and microenvironment but also have adverse effects in stem cell cultures, whereas PDX are expensive with a low transplantation success rate and require a long culture time. In recent years, advances in three-dimensional (3D) organoid culture technology have led to the development of novel physiological systems that model the tissues of origin more precisely than traditional culture methods. Patient-derived cancer organoids bridge the conventional gaps in PDC and PDX models and closely reflect the pathophysiological features of natural tumorigenesis and metastasis, and have led to new patient-specific drug screening techniques, development of individualized treatment regimens, and discovery of prognostic biomarkers and mechanisms of resistance. Synergistic combinations of cancer organoids with other technologies, for example, organ-on-a-chip, 3D bio-printing, and CRISPR-Cas9-mediated homology-independent organoid transgenesis, and with treatments, such as immunotherapy, have been useful in overcoming their limitations and led to the development of more suitable model systems that recapitulate the complex stroma of cancer, inter-organ and intra-organ communications, and potentially multiorgan metastasis. In this review, we discuss various methods for the creation of organ-specific cancer organoids and summarize organ-specific advances and applications, synergistic technologies, and treatments as well as current limitations and future prospects for cancer organoids. Further advances will bring this novel 3D organoid culture technique closer to clinical practice in the future.

Keywords: 3D bio-printing; cancer organoids; cancer stroma; drug screening; organ-on-a-chip; personalized medicine; prognostic biomarker; tumor microenvironment.

FIGURE 1

Summary of the procedures used to establish normal tissue and cancer organoids. Induced pluripotent stem cells, somatic stem cells, and embryonic stem cells can be used to establish normal tissue‐derived organoids. Patient‐derived cancer cells can be used to establish in vivo xenografts or can be propagated on an enriched Matrigel matrix and cultured into three‐dimensional tumor organoids that have in vivo and in vitro applications. Abbreviations: ESCs, embryonic stem cells; iPSCs, induced pluripotent stem cells

FIGURE 2

Various applications of tumor‐derived organoids in tumor modeling, drug screening, precision medicine, tumor immunotherapy, and gene profiling. Organoid technology can be used to model a variety of human cancers, to test drug efficacy and toxicity in precision medicine, and to develop novel targeted therapeutics. Furthermore, organoid biobanks can be used for academic studies and gene profiling of various cancers. Moreover, synergistic application with CRISPR/Cas9 gene editing can be used to further elucidate the pathophysiology of various cancers and to study the effects of specific genetic changes on tissue function and the development of disease

FIGURE 3

Advance in technology and current limitations of organoids for cancer therapy. Synergistic applications of cancer organoids with novel technologies include organ‐on‐a‐chip, 3D bio‐printing, and CRISPR‐HOT. These synergistic technologies with cancer organoids underwent testing at the molecular and cellular levels and in animal models and were ultimately investigated in various cancers. At present, the main limitations of cancer organoids for cancer research are their variable reproducibility, failure to reconstitute the microenvironment, the unwanted effects of the ECM, lack of standardized protocols, high cost, and absence of vascular elements. ECM, extracellular matrix; CRISPR‐HOT, CRISPR‐Cas9‐mediated homology‐independent organoid transgenesis