Patient-derived xenograft models in cancer therapy: technologies and applications

Abstract

Patient-derived xenograft (PDX) models, in which tumor tissues from patients are implanted into immunocompromised or humanized mice, have shown superiority in recapitulating the characteristics of cancer, such as the spatial structure of cancer and the intratumor heterogeneity of cancer. Moreover, PDX models retain the genomic features of patients across different stages, subtypes, and diversified treatment backgrounds. Optimized PDX engraftment procedures and modern technologies such as multi-omics and deep learning have enabled a more comprehensive depiction of the PDX molecular landscape and boosted the utilization of PDX models. These irreplaceable advantages make PDX models an ideal choice in cancer treatment studies, such as preclinical trials of novel drugs, validating novel drug combinations, screening drug-sensitive patients, and exploring drug resistance mechanisms. In this review, we gave an overview of the history of PDX models and the process of PDX model establishment. Subsequently, the review presents the strengths and weaknesses of PDX models and highlights the integration of novel technologies in PDX model research. Finally, we delineated the broad application of PDX models in chemotherapy, targeted therapy, immunotherapy, and other novel therapies.

Fig. 1

PDX in the new era of cancer treatment. This figure shows the current conundrums of cancer treatment including restricted beneficiaries, tumor heterogeneity, drug resistance as well as tumor metastasis and recurrence, and shows the versatile functions of PDX in developing therapeutics against cancer

Fig. 2

The brief timeline of milestones in PDX study

Fig. 3

The establishment of PDX. a Showing the establishment process of PDX. b Showing the factors affecting the engraftment rate and the categories of PDX mice

Fig. 4

The advantages of PDX over other models. a PDX could preserve the genetic landscape, morphology and phenotype of the parental tumor. b PDX could maintain tumor heterogeneity and specific traits of metastases. c The realization of cancer-immune interaction in humanized PDX: human immune system tends to be educated by tumor and exhibits an exhausted status over time, and tumors maintain evolution and heterogeneity to survive with upregulated immunosuppressive molecules and decreased production of human pro-inflammatory cytokines. d PDX could reproduce the drug response observed in patients

Fig. 5

The weaknesses existing in current PDX models. a Tumor stroma tends to be replaced by murine-derived ECM and stromal cells after several passages, which hinders immune cell activation without human cytokine secretion. b Loss of subclones heterogeneity during the establishment and passage of PDX. c PDX mice have a relatively high risk of spontaneous lymphoma which could cover up accurate results due to the distinct drug sensitivities between lymphoma and other tumors