Abstract
BackgroundAccurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days.MethodsUsing a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients.ResultsThe resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days.ConclusionsWe conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.
Highlights
Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy
The samples were derived from a representative mix of approximately 2/3 males and 1/3 females and at different TNM-stages upon diagnosis including 13 without lymph node involvement, 20 with lymph node involvement and 6 where such information was not available (Supplemental Table 1)
Using 5 metastasized cells as the cut-off, the zebrafish tumor xenograft (ZTX)-test exhibited a sensitivity of 100% and specificity of 53% which is significantly more accurate compared to the differentiation predictor. These findings strongly suggest that ZTX models generated from cryopreserved Patient-derived xenograft (PDX) material closely recapitulate invasive phenotypes of the patient tumors and predict lymph node involvement with higher sensitivity than the current clinical gold standard
Summary
Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Cancer patients exhibit highly individual variations in treatment outcome and tumor invasiveness, the cause of which are poorly understood [1]. These variations complicate effective personalized treatment planning, which in turn is important for ensuring successful treatment. Patients with Stage 2 cancer where local invasion of tumor cells into surrounding tissues is associated with an increased risk of tumor dissemination to the lymph nodes, can be considered either for direct surgery [1] or for neoadjuvant (i.e. pre-surgical) chemotherapy. Medical treatment planning depends on an understanding of the extent of tumor dissemination
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