Related Experiment Video
Updated: Feb 18, 2026
The Establishment and Utilization of Patient Derived Xenograft Models of Central Nervous System Metastasis
Published on: May 7, 2021
Development of Novel Patient-Derived Xenografts from Breast Cancer Brain Metastases
María J Contreras-Zárate1, D Ryan Ormond2, Austin E Gillen3
1Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Abstract:
Brain metastases are an increasing burden among breast cancer patients, particularly for those with HER2+ and triple negative (TN) subtypes. Mechanistic insight into the pathophysiology of brain metastases and preclinical validation of therapies has relied almost exclusively on intracardiac injection of brain-homing cells derived from highly aggressive TN MDA-MB-231 and HER2+ BT474 breast cancer cell lines. Yet, these well characterized models are far from representing the tumor heterogeneity observed clinically and, due to their fast progression in vivo, their suitability to validate therapies for established brain metastasis remains limited. The goal of this study was to develop and characterize novel human brain metastasis breast cancer patient-derived xenografts (BM-PDXs) to study the biology of brain metastasis and to serve as tools for testing novel therapeutic approaches. We obtained freshly resected brain metastases from consenting donors with breast cancer. Tissue was immediately implanted in the mammary fat pad of female immunocompromised mice and expanded as BM-PDXs. Brain metastases from 3/4 (75%) TN, 1/1 (100%) estrogen receptor positive (ER+), and 5/9 (55.5%) HER2+ clinical subtypes were established as transplantable BM-PDXs. To facilitate tracking of metastatic dissemination using BM-PDXs, we labeled PDX-dissociated cells with EGFP-luciferase followed by reimplantation in mice, and generated a BM-derived cell line (F2-7). Immunohistologic analyses demonstrated that parental and labeled BM-PDXs retained expression of critical clinical markers such as ER, progesterone receptor, epidermal growth factor receptor, HER2, and the basal cell marker cytokeratin 5. Similarly, RNA sequencing analysis showed clustering of parental, labeled BM-PDXs and their corresponding cell line derivative. Intracardiac injection of dissociated cells from BM-E22-1, resulted in magnetic resonance imaging-detectable macrometastases in 4/8 (50%) and micrometastases (8/8) (100%) mice, suggesting that BM-PDXs remain capable of colonizing the brain at high frequencies. Brain metastases developed 8-12 weeks after ic injection, located to the brain parenchyma, grew around blood vessels, and elicited astroglia activation characteristic of breast cancer brain metastasis. These novel BM-PDXs represent heterogeneous and clinically relevant models to study mechanisms of brain metastatic colonization, with the added benefit of a slower progression rate that makes them suitable for preclinical testing of drugs in therapeutic settings.
Insights
Researchers developed new human breast cancer brain metastasis patient-derived xenografts (BM-PDXs). These models better represent tumor diversity and are suitable for testing new therapies for brain metastases.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Brain metastases are a significant clinical challenge in breast cancer, especially for HER2-positive (HER2+) and triple-negative (TN) subtypes.
- Current preclinical models, often derived from cell lines, lack the heterogeneity of human tumors and progress too rapidly for therapy validation.
Purpose of the Study:
- To develop and characterize novel human breast cancer brain metastasis patient-derived xenografts (BM-PDXs).
- To establish clinically relevant models for studying brain metastasis biology and evaluating therapeutic strategies.
Main Methods:
- Resected human brain metastases were implanted in mice and expanded as BM-PDXs.
- PDX cells were labeled (EGFP-luciferase) for tracking, and a cell line was derived.
- Immunohistology and RNA sequencing confirmed marker expression and genetic similarity.
- Intracardiac injection of BM-PDX cells induced brain metastases in mice.
Main Results:
- Successful establishment of BM-PDXs from TN, ER+, and HER2+ breast cancer subtypes.
- BM-PDXs retained key clinical marker expression (ER, HER2, etc.).
- Intracardiac injection led to detectable brain macrometastases and micrometastases.
- Developed metastases showed characteristic features like perivascular growth and astroglia activation.
Conclusions:
- Novel BM-PDXs offer heterogeneous and clinically relevant models for brain metastasis research.
- These models enable the study of brain metastatic colonization mechanisms.
- Slower progression rates make BM-PDXs suitable for preclinical drug testing in established brain metastases.
