PUBLICATION
Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer
- Authors
- Ali, Z., Vildevall, M., Rodriguez, G.V., Tandiono, D., Vamvakaris, I., Evangelou, G., Lolas, G., Syrigos, K.N., Villanueva, A., Wick, M., Omar, S., Erkstam, A., Schueler, J., Fahlgren, A., Jensen, L.D.
- ID
- ZDB-PUB-220211-1
- Date
- 2022
- Source
- Journal of experimental & clinical cancer research : CR 41: 58 (Journal)
- Registered Authors
- Keywords
- Cancer, Dissemination, Drug response, Lymph node, Metastasis, PDX, Xenograft, ZTX, Zebrafish
- MeSH Terms
-
- Animals
- Carcinoma, Non-Small-Cell Lung/drug therapy*
- Carcinoma, Non-Small-Cell Lung/pathology
- Disease Models, Animal
- Humans
- Lung Neoplasms/drug therapy*
- Lung Neoplasms/pathology
- Lymph Nodes/pathology*
- Neoplasm Metastasis
- Treatment Outcome
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 35139880 Full text @ J. Exp. Clin. Cancer Res.
Citation
Ali, Z., Vildevall, M., Rodriguez, G.V., Tandiono, D., Vamvakaris, I., Evangelou, G., Lolas, G., Syrigos, K.N., Villanueva, A., Wick, M., Omar, S., Erkstam, A., Schueler, J., Fahlgren, A., Jensen, L.D. (2022) Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer. Journal of experimental & clinical cancer research : CR. 41:58.
Abstract
Background Accurate 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.
Methods Using 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.
Results The 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.
Conclusions We 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping