Setting up a wide panel of patient‐derived tumor xenografts of non–small cell lung cancer by improving the preanalytical steps

Abstract

With the ongoing need to improve therapy for non–small cell lung cancer (NSCLC) there has been increasing interest in developing reliable preclinical models to test novel therapeutics. Patient-derived tumor xenografts (PDX) are considered to be interesting candidates. However, the establishment of such model systems requires highly specialized research facilities and introduces logistic challenges. We aimed to establish an extensive well-characterized panel of NSCLC xenograft models in the context of a long-distance research network after careful control of the preanalytical steps. One hundred fresh surgically resected NSCLC specimens were shipped in survival medium at room temperature from a hospital-integrated biobank to animal facilities. Within 24 h post-surgery, tumor fragments were subcutaneously xenografted into immunodeficient mice. PDX characterization was performed by histopathological, immunohistochemical, aCGH and next-generation sequencing approaches. For this model system, the tumor take rate was 35%, with higher rates for squamous carcinoma (60%) than for adenocarcinoma (13%). Patients for whom PDX tumors were obtained had a significantly shorter disease-free survival (DFS) compared to patients for whom no PDX tumors (P = 0.039) were obtained. We established a large panel of PDX NSCLC models with a high frequency of mutations (29%) in EGFR, KRAS, NRAS, MEK1, BRAF, PTEN, and PI3KCA genes and with gene amplification (20%) of c-MET and FGFR1. This new patient-derived NSCLC xenograft collection, established regardless of the considerable time required and the distance between the clinic and the animal facilities, recapitulated the histopathology and molecular diversity of NSCLC and provides stable and reliable preclinical models for human lung cancer research.

Tumor characteristics associated with engraftment of patient‐derived non–small cell lung cancer xenografts in immunocompromised mice

“…2,33 We also found that residual tumor tissue obtained from mice in which PDXs had not formed at ≥12 months after implantation of primary tumors often contained human CD8+ and/or CD20+ immune cells, indicating that the coimplantation of tumor-infiltrating immune cells with fresh tumor samples might be one of the factors preventing PDX growth in immunodeficient mice. Our analysis of PDX engraftment from surgically resected tumor specimens from 308 patients with NSCLC found an overall engraftment rate of approximately 35% in NSG mice.…”

“…2,33 The proliferation of EBV-positive B cells in tumor samples also has been reported to result in the formation of human B-cell lymphomas and the failure of PDX growth in specimens from patients with several types of cancer, including lung cancer. 2,33 The proliferation of EBV-positive B cells in tumor samples also has been reported to result in the formation of human B-cell lymphomas and the failure of PDX growth in specimens from patients with several types of cancer, including lung cancer.…”

Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors

“…However, it is still unclear to what extent they fully recapitulate the genetic, epigenetic, and signaling mechanisms that collectively drive clinical disease, especially for their matched patient tumors. At a broad level, PDXs harbor similar NSCLC profiles of gene copy number, mRNA and protein, and retain specific “driver” mutations of the matching primary tumors . Here, we now report the high concordance of genome‐wide exomic single nucleotide variants (SNVs) and gene copy number variants (CNVs) between 25 PDXs and their matched patient tumors, which comprehensively establishes the ability of PDXs to faithfully recapitulate the genetic mechanisms driving pathobiology of their specific corresponding patient tumors.…”

Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

“…Consequently, some cancers, such as neuroendocrine, luminal ER+ breast, and prostate cancers (Rosfjord et al, 2014) are underrepresented. Notably, PDX engraftibility appears to significantly correlate with clinical aggressiveness (Ilie et al, 2015 ).…”