Related Experiment Video
Updated: Aug 21, 2025
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Genomic and transcriptomic analysis of a diffuse pleural mesothelioma patient-derived xenograft library
Michael Offin1,2, Jennifer L Sauter3, Sam E Tischfield4
1Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Background:
Diffuse pleural mesothelioma (DPM) is an aggressive malignancy that, despite recent treatment advances, has unacceptably poor outcomes. Therapeutic research in DPM is inhibited by a paucity of preclinical models that faithfully recapitulate the human disease.
Methods:
We established 22 patient-derived xenografts (PDX) from 22 patients with DPM and performed multi-omic analyses to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these PDX models and compared features to those of the matched primary patient tumors. Targeted next-generation sequencing (NGS; MSK-IMPACT), immunohistochemistry, and histologic subtyping were performed on all available samples. RNA sequencing was performed on all available PDX samples. Clinical outcomes and treatment history were annotated for all patients. Platinum-doublet progression-free survival (PFS) was determined from the start of chemotherapy until radiographic/clinical progression and grouped into < or ≥ 6 months.
Results:
PDX models were established from both treatment naïve and previously treated samples and were noted to closely resemble the histology, genomic landscape, and proteomic profiles of the parent tumor. After establishing the validity of the models, transcriptomic analyses demonstrated overexpression in WNT/β-catenin, hedgehog, and TGF-β signaling and a consistent suppression of immune-related signaling in PDXs derived from patients with worse clinical outcomes.
Conclusions:
These data demonstrate that DPM PDX models closely resemble the genotype and phenotype of parental tumors, and identify pathways altered in DPM for future exploration in preclinical studies.
Insights
Researchers developed patient-derived xenograft (PDX) models for diffuse pleural mesothelioma (DPM). These models accurately reflect human tumors, aiding the study of DPM's molecular landscape and potential therapeutic targets.
Area of Science:
- Oncology
- Translational Research
- Genomics
Background:
- Diffuse pleural mesothelioma (DPM) is an aggressive cancer with poor outcomes.
- Current treatment advances have not significantly improved patient survival.
- A lack of accurate preclinical models hinders therapeutic research in DPM.
Purpose of the Study:
- To establish and validate patient-derived xenograft (PDX) models for diffuse pleural mesothelioma (DPM).
- To characterize the molecular and genomic features of DPM PDX models.
- To compare DPM PDX models with their matched primary patient tumors.
Main Methods:
- 22 DPM patient-derived xenografts (PDX) were established.
- Multi-omic analyses including targeted next-generation sequencing (NGS) and RNA sequencing were performed.
- Histology, proteomic profiles, and clinical outcomes were analyzed.
Main Results:
- PDX models closely mirrored the histology, genomic landscape, and proteomic profiles of the original tumors.
- Transcriptomic analysis revealed overexpression of WNT/β-catenin, hedgehog, and TGF-β signaling pathways.
- Suppression of immune-related signaling was observed in PDXs from patients with poorer outcomes.
Conclusions:
- DPM PDX models accurately represent the genotype and phenotype of parental tumors.
- These validated models provide a valuable preclinical tool for DPM research.
- Identified signaling pathways offer potential targets for future DPM therapeutic strategies.
