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Updated: Jun 5, 2025
High-Throughput Dissociation and Orthotopic Implantation of Breast Cancer Patient-Derived Xenografts
Published on: December 20, 2024
An annotated biobank of triple negative breast cancer patient-derived xenografts featuring treatment-naïve and
Abstract:
Triple negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial ( NCT02276443 ) at MD Anderson Cancer Center, including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of PDX models were capable of lung metastasis. Comprehensive molecular profiling demonstrated conservation of genomes and transcriptomes between patient and corresponding PDX tumors, with representation of all major transcriptional subtypes. Transcriptional changes observed in the longitudinal PDX models highlight dysregulation in pathways associated with DNA integrity, extracellular matrix interactions, the ubiquitin-proteasome system, epigenetics, and inflammatory signaling. These alterations reveal a complex network of adaptations associated with chemoresistance. This PDX biobank provides a valuable resource for tackling the most pressing issues facing the clinical management of TNBC, namely chemoresistance and metastasis.
Insights
Developing new treatments for triple negative breast cancer (TNBC) requires better models. This study created a patient-derived xenograft (PDX) biobank to study chemoresistant TNBC and metastasis.
Area of Science:
- Oncology
- Translational Research
- Cancer Models
Background:
- Triple negative breast cancer (TNBC) poses significant challenges, particularly when resistant to neoadjuvant chemotherapy (NACT).
- Effective treatment strategies for chemoresistant TNBC necessitate experimental models that accurately reflect its inherent heterogeneity.
- Patient-derived xenografts (PDX) are crucial for studying complex cancer biology and treatment responses.
Purpose of the Study:
- To establish a comprehensive biobank of TNBC patient-derived xenograft (PDX) models.
- To characterize these models for their ability to recapitulate TNBC heterogeneity, chemoresistance, and metastatic potential.
- To provide a valuable resource for investigating therapeutic strategies against chemoresistant and metastatic TNBC.
Main Methods:
- Creation of 92 orthotopic PDX models from 75 TNBC patients in the ARTEMIS clinical trial.
- Inclusion of 12 longitudinal PDX model sets from serial biopsies during NACT and from metastatic sites.
- Comprehensive molecular profiling (genomic and transcriptomic) of PDX models and comparison with patient tumors.
Main Results:
- The PDX biobank includes models from both chemosensitive and chemoresistant tumors, with ~30% exhibiting lung metastasis capability.
- Molecular profiling confirmed high conservation of genomic and transcriptomic profiles between patient tumors and their corresponding PDX models.
- Longitudinal models revealed significant transcriptional alterations in pathways related to DNA integrity, extracellular matrix, ubiquitin-proteasome system, epigenetics, and inflammation, indicative of chemoresistance adaptations.
Conclusions:
- The established TNBC PDX biobank accurately represents tumor heterogeneity and key biological features, including chemoresistance and metastasis.
- These PDX models serve as a powerful preclinical tool for dissecting the mechanisms of chemoresistance and identifying novel therapeutic targets.
- This resource will accelerate the development of effective treatments for patients with advanced and treatment-refractory triple negative breast cancer.
