Applications of patient-derived tumor xenograft models and tumor organoids

Abstract

Patient-derived tumor xenografts (PDXs), in which tumor fragments surgically dissected from cancer patients are directly transplanted into immunodeficient mice, have emerged as a useful model for translational research aimed at facilitating precision medicine. PDX susceptibility to anti-cancer drugs is closely correlated with clinical data in patients, from whom PDX models have been derived. Accumulating evidence suggests that PDX models are highly effective in predicting the efficacy of both conventional and novel anti-cancer therapeutics. This also allows "co-clinical trials," in which pre-clinical investigations in vivo and clinical trials could be performed in parallel or sequentially to assess drug efficacy in patients and PDXs. However, tumor heterogeneity present in PDX models and in the original tumor samples constitutes an obstacle for application of PDX models. Moreover, human stromal cells originally present in tumors dissected from patients are gradually replaced by host stromal cells as the xenograft grows. This replacement by murine stroma could preclude analysis of human tumor-stroma interactions, as some mouse stromal cytokines might not affect human carcinoma cells in PDX models. The present review highlights the biological and clinical significance of PDX models and three-dimensional patient-derived tumor organoid cultures of several kinds of solid tumors, such as those of the colon, pancreas, brain, breast, lung, skin, and ovary.

Keywords: Acquired resistance; Avatar models; Carcinoma-associated fibroblasts; Co-clinical trials; Heterogeneity; Immunodeficient mice; Organoids; PDX models; Translational research; Tumor microenvironment.

Fig. 1

Identification of optimal therapeutics using PDX mouse clinical trials. PDX models are potentially useful when the optimal course of treatment cannot be readily determined for individual patients. For instance, in the illustration, there are three patients (A-C) with gastric cancer, who hope to receive treatment with the novel therapy drug X if its therapeutic efficacy is proven. In this case, it would be time-consuming and require significant clinical risk to compare the therapeutic response to conventional drugs and the new drug X without “co-clinical trials.” While xenografts derived from patient A respond to drug X, xenografts derived from patient C respond to conventional treatments, but not drug X (step 1). Contrastingly, patient B–derived xenografts partially respond to both therapeutics. This pre-clinical screening by an avatar model is helpful to determine which treatment would have the optimal outcome in each patient (step 2)

Fig. 2

High-sensitivity detection of distant micrometastases of PDX-derived organoids by GFP transduction. After a primary colorectal adenocarcinoma (CRC) diagnosed as a moderately differentiated type was surgically resected, CRC cells were subcutaneously implanted into NOG mice to establish a PDX model. PDX tissue was treated with collagenase to obtain tumor cell suspension. CRC organoids were then established from PDX tissue and expanded in three-dimensional culture using the artificial extracellular matrix after infection with GFP lentivirus. These GFP-labelled organoids implanted orthotopically revealed distant micrometastases in the lungs within 3 months [56]