Molecular profiling of patient-derived breast cancer xenografts

Abstract

IntroductionIdentification of new therapeutic agents for breast cancer (BC) requires preclinical models that reproduce the molecular characteristics of their respective clinical tumors. In this work, we analyzed the genomic and gene expression profiles of human BC xenografts and the corresponding patient tumors.MethodsEighteen BC xenografts were obtained by grafting tumor fragments from patients into Swiss nude mice. Molecular characterization of patient tumors and xenografts was performed by DNA copy number analysis and gene expression analysis using Affymetrix Microarrays.ResultsComparison analysis showed that 14/18 pairs of tumors shared more than 56% of copy number alterations (CNA). Unsupervised hierarchical clustering analysis showed that 16/18 pairs segregated together, confirming the similarity between tumor pairs. Analysis of recurrent CNA changes between patient tumors and xenografts showed losses in 176 chromosomal regions and gains in 202 chromosomal regions. Gene expression profile analysis showed that less than 5% of genes had recurrent variations between patient tumors and their respective xenografts; these genes largely corresponded to human stromal compartment genes. Finally, analysis of different passages of the same tumor showed that sequential mouse-to-mouse tumor grafts did not affect genomic rearrangements or gene expression profiles, suggesting genetic stability of these models over time.ConclusionsThis panel of human BC xenografts maintains the overall genomic and gene expression profile of the corresponding patient tumors and remains stable throughout sequential in vivo generations. The observed genomic profile and gene expression differences appear to be due to the loss of human stromal genes. These xenografts, therefore, represent a validated model for preclinical investigation of new therapeutic agents.

Primary esophageal and gastro-esophageal junction cancer xenograft models: clinicopathological features and engraftment

“…Though few studies have focused on the genomic similarities of patient tissue and primary xenografts, those published suggest that mutations are generally conserved. 15,16 In addition, because these models are established under more physiological conditions (ie, temperature, oxygen levels, nutrient content etc. ), they may be appropriate for representing human cancers in specific settings.…”

Contribution au développement de nouvelles thérapies contre le cancer colorectal

“…L'analyse en classification non supervisée a montré la remarquable stabilité génomique des xénogreffes de cancers colorectaux pendant les dix premiers passages au moins. Cette caractéristique a d'ailleurs déjà été observée pour d'autres séries de xéno-greffes [6,7]. Cependant, l'apparition de quelques altérations de novo, absentes dans les tumeurs d'origine, pourrait s'expliquer par l'expansion clonale d'une population minoritaire et/ou par la poursuite dans la xénogreffe du processus de mutation qui avait commencé dans la tumeur issue du patient.…”

Patient-derived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century

“…In contrast to in vitro propagated cultures, cytogenetic analyses of PDX models reveals strong preservation of the chromosomal architecture observed in patient tumors. 28,62 PDX models of melanoma, breast, pancreatic, ovarian, lung, colorectal, and brain-derived tumors have been successfully established in many laboratories (reviewed by Tentler et al 29 ), and many have proven to exhibit similar chemoresponsiveness to anti-neoplastic agents as observed in the same donating patient in the clinicunderscoring the fidelity of these models to the natural disease state 30,63 (unpublished results).…”

“…First, patient-derived xenograft (PDX) tumor models are increasingly feasible and available. [26][27][28][29] Second, evidence is amassing that supports the cancer stem cell (CSC) paradigm: a theoretical model for cancer that accounts for the importance of specific tumor cell subpopulations to a tumor's growth and potential for driving tumor recurrence (reviewed in previous studies [30][31][32] ). Finally, next-generation DNA and RNA sequencing efforts (eg, The Cancer Genome Atlas) have demonstrated that very few common mutations unite particular solid tumor types; rather, patient tumors have a spectrum of mutations that collectively drive tumor growth.…”

“…60 To better preserve the genomic integrity and tumor heterogeneity observed in patients, many researchers are increasingly turning to PDX models generated using freshly resected patient tumors immediately transplanted into immunocompromised murine hosts without an intermediate in vitro culture step. 26,28,42 Serial passage and expansion of tumors through successive generations of murine hosts without intervening cell culture permits ongoing propagation of tumor lines and the study of tumor biology without subjecting PDX tumor cells to the stressful and compromising conditions encountered in vitro. 42 Currently, subcutaneous PDX models, wherein tumor cells are transplanted underneath the skin of the hindquarters or in the mammary fat pad dominate the field of primary xenografts, succeeding intra-ocular, embryonic, and athymic systems.…”