Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal malignancy, with an average 5-year survival rate of 9% (Siegel RL, Miller KD, Jemal A. Ca Cancer J Clin. 2019;69(1):7-34). The steady increase in mortality rate indicates limited efficacy of the conventional regimen. The heterogeneity of PDAC calls for personalized treatment in clinical practice, which requires the construction of a preclinical system for generating patient-derived models. Currently, the lack of high-quality preclinical models results in ineffective translation of novel targeted therapeutics. This review summarizes applications of commonly used models, discusses major difficulties in PDAC model construction and provides recommendations for integrating workflows for precision medicine.

Keywords: Pancreatic cancer; Precision medicine; Preclinical model.

Fig. 1

Difficulties in the preclinical modeling of PDAC. Figure was produced using Servier Medical Art (http://smart.servier.com/). a When establishing a preclinical model library, intertumoral heterogeneity at the multiomic level highlights the significance of cohort size, while intratumoral heterogeneity in temporal (subclonal evolution) and spatial (primary tumor and metastasis) dimension requires multiple sampling from individuals. b Complex tumor-stroma interactions and phenotypical heterogeneity of stromal components are major barriers to the recapitulation of the TME. Low immunogenicity and the immunosuppressive sanctuary of PDAC are also difficult for preclinical modeling. c Serial passaging of preclinical models enables the selection of malignant subclones of tumor cells, raising doubts on the application of cells from later passages. (10), (11), (12) and (13) denote reference [–13], respectively. PDAC, pancreatic ductal adenocarcinoma; TME, tumor microenvironment; CAF, cancer-associated fibroblast; PSC, pancreatic stellate cell; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell

Fig. 2

Choices of preclinical models for use in preclinical studies and precision medicine of PDAC. Figure was produced using Servier Medical Art (http://smart.servier.com/). Clonal and expandable models are used in basic researches to decipher the molecular mechanism of distinct tumor behavior. Cell line or organoid-based co-culture of PDAC with TME components could be exploited in study of tumor-stoma interaction. As a core target of translational research, the prediction of genotype-drug response mainly relies on model-specific high-throughput sequencing and drug screening. Recently, more focus has been directed to personalized therapy development based on patient-derived cell lines, organoids and xenografts. 3D models excel 2D cell culture in structural and physiological consistency with naturally growing tumor and will play a more important role in precision medicine of PDAC. Of all the preclinical models, use of early passages could minimize genetic and functional drift away from the primary tumor. PDAC, pancreatic ductal adenocarcinoma; CAF, cancer-associated fibroblast; TIL, tumor infiltrating lymphocyte; iPSC, induced pluripotent stem cell; GEMM, genetically engineered mouse model; PDCL, patient-derived cell line; PDO, patient-derived organoid; PDX, patient-derived xenograft