Τίτλος:
Zebrafish patient-derived xenograft models predict lymph node
involvement and treatment outcome in non-small cell lung cancer
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Ali, Zaheer
Vildevall, Malin
Rodriguez, Gabriela Vazquez and
Tandiono, Decky
Vamvakaris, Ioannis
Evangelou, Georgios and
Lolas, Georgios
Syrigos, Konstantinos N.
Villanueva, Alberto and
Wick, Michael
Omar, Shenga
Erkstam, Anna
Schueler, Julia and
Fahlgren, Anna
Jensen, Lasse D.
Περιοδικό:
Journal of Experimental & Clinical Cancer Research
Λέξεις-κλειδιά:
Cancer; Zebrafish; Metastasis; Dissemination; Drug response; Xenograft;
Lymph node; PDX; ZTX
DOI:
10.1186/s13046-022-02280-x
