Dataset Information

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.

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.

SUBMITTER: Ali Z

PROVIDER: S-EPMC8827197 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.

Ali Zaheer Z Vildevall Malin M Rodriguez Gabriela Vazquez GV Tandiono Decky D Vamvakaris Ioannis I Evangelou Georgios G Lolas Georgios G Syrigos Konstantinos N KN Villanueva Alberto A Wick Michael M Omar Shenga S Erkstam Anna A Schueler Julia J Fahlgren Anna A Jensen Lasse D LD

Journal of experimental & clinical cancer research : CR 20220209 1

<h4>Background</h4>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 treat ...[more]

PMID: 35139880

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Project description:BackgroundThe diagnosis of proximal small bowel involvement in Crohn's disease (CD) can be challenging at magnetic resonance enterography (MRE). The inflammatory process in CD can be associated with peri-intestinal inflammatory reactions, including the presence of inflamed mesenteric lymph nodes.ObjectivesTo evaluate the significance of inflamed mesenteric lymph nodes adjacent to the jejunum at MRE in CD and the association with proximal bowel disease as detected by video capsule endoscopy (VCE).DesignThis retrospective study was performed in two tertiary medical centres, and included 64 patients with CD who underwent MRE as well as VCE within 1 year.MethodsData were collected for examinations performed between August 2013 and February 2021. MRE images were independently reviewed by radiologists who were blinded to the clinical data. Association between the presence of mesenteric lymph nodes adjacent to jejunum at MRE and disease activity according to VCE Lewis scores of proximal small bowel was examined.ResultsVCE detected proximal disease in 24/64 patients (37.5%). Presence of regional lymph nodes in the jejunal mesentery was significantly associated with jejunal disease as seen on VCE (p < 0.001). Of the 20 patients who had proximal mesenteric lymph nodes at MRE, 15 (75%) had jejunal disease at VCE (sensitivity, 62.5%; specificity, 87.5%; and negative and positive predictive values, 79.5 and 75%, respectively). The number of regional lymph nodes was positively correlated with jejunal disease (mean: 2.63 ± 2.90 versus 0.78 ± 2.60, p = 0.01). Other MRE features of lymph nodes were not significantly predictive of jejunal CD.ConclusionIn patients with CD, inflamed regional lymph nodes in the jejunal mesentery at MRE can be valuable to suggest proximal small bowel disease, even when bowel wall features at imaging do not suggest disease involvement.Plain language summaryThe diagnosis of proximal small bowel involvement in Crohn's disease (CD) can be challenging at magnetic resonance enterography (MRE). We analysed MRE examinations in patients with CD for the presence of lymph nodes adjacent to the proximal small bowel. We included 64 patients with CD who had MRE examinations and video capsule endoscopy (VCE) examinations within 1 year. Of 64 patients, 24 had proximal small bowel disease according to VCE. We found that of 20 patients who had regional mesenteric lymph nodes in the jejunal mesentery at MRE, 15 had proximal bowel disease involvement. We also found that patients with jejunal disease had a larger number of regional lymph nodes compared to patients without jejunal disease. All but one patient had normal appearing bowel at MRE. But, using regional mesenteric lymphadenopathy at MRE as an indicator for disease, 15/24 (62.5%) patients with proximal small bowel disease were detected. We therefore conclude that regional mesenteric lymph nodes assessment at MRE can aid diagnose proximal bowel disease, even when the proximal bowel looks normal at imaging. Presence of proximal mesenteric lymph nodes at MRE in patients with CD possibly warrant further investigation of the proximal small bowel by endoscopic measures.

Dataset Information

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.

Background

Methods

Results

Conclusions

Publications

Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer.

Similar Datasets

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