Multiregion Genomic Analysis of Serially Transplanted Patient-derived Xenograft Tumors

Abstract

Background: Intratumoral heterogeneity (ITH) is a major cause underlying therapeutic difficulty of cancer. Although an understanding of ITH is critically important in order to develop novel therapeutic strategies, experimental models that enable the examination of ITH in a time series are lacking. Materials and Methods: We developed an experimental approach based on patient-derived xenograft (PDX) mice and a multiregional sequencing approach (MRA). The multiple regions of primary colorectal cancer (CRC) and serially transplanted PDX tumors were analyzed via whole-exome sequencing and bioinformatic analyses. Results: Our PDX-MRA of CRC indicated the spatiotemporal genetic transition of ITH. It was found that the subclonal architecture of CRC dynamically changes during serial transplantation. Furthermore, our data suggest that environmental selective pressures drive the development of minor pre-existing subclones in PDX-MRA. Conclusion: PDX-MRA is a useful tool for understanding the spatiotemporal dynamics of ITH. Cancer consists of multiple subclones with different genetic backgrounds (1). This intratumoral heterogeneity (ITH) is a major cause of the therapeutic difficulty because the presence of multiple subclones boosts adaptation to pharmacological 21 This article is freely accessible online.

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…A recent study in colorectal carcinoma (CRC) by Sato et al . also showed the acquisition of CNAs in PDX tumors compared to parental tumors, including chromosome 18q deletion and chromosome 20 amplification . A study of head and neck squamous cell carcinomas detected genetic SMAD4 loss in PDX models and a derived cell line …”

“…In some cancer types (e.g., primary human head and neck squamous cell carcinoma, salivary gland adenoid cystic carcinoma and cervical carcinoma), later‐passage PDX tumors have decreased latency to harvest, elevated nuclear pleomorphism and altered mitosis patterns, indicating increased proliferation ability . In addition, the tumor growth rate positively correlates with passage number . Interestingly, the growth rate of serial transplanted xenograft tumors is exponential rather than proportional based on relative tumor volume …”

“…Moreover, some subclones completely disappear during the serial transplantation of PDX models, and others become dominant (Fig. ) …”

“…Recently, Sato et al . delineated different clonal architecture among the same original Passage 1 PDX models based on multiregional analysis to infer the genome of the subclones . In a study of one patient with high‐risk neuroblastoma, a total of 10 patient‐derived orthotopic xenograft (PDOX) tumors were established via dissection.…”

“…Additionally, restoration of the dominant subclone of serially transplanted PDX models provides evidence that ITH‐based selection bias can also occur during the serial transplantation of PDX models . In detail, partly resected tumor fragments from early generations do not retain the exact same clonal composition as the entire xenograft tumor, which is akin to the engraftment process of PDX models.…”