Brain metastasis patient-derived xenograft models to characterize the contribution of brain microenvironment to metastatic outgrowth

Sep 29, 2026

Brain metastasis drives a high-risk cancer relapse and urgently requires clinically relevant preclinical mouse models and improved therapeutic strategies. Patient-derived xenograft (PDX) models offer translational relevance, while brain stromal cells critically influence metastatic initiation and outgrowth. The study compares ectopic and orthotopic brain metastasis PDX models to determine whether the brain microenvironment alters therapeutic efficacy of a PPARγ antagonist.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages12

Reading Time30 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Key Points

Importance of the Study

Neuro-Oncology Advances 1 7(1), vdaf239, 2025 | [https://doi.org/10.1093/noajnl/vdaf239 | Advance Access](https://doi.org/10.1093/noajnl/vdaf239 | Advance Access) publication November 19, 2025 Brain metastasis patient-derived xenograft models to characterize the contribution of brain microenvironment to metastatic outgrowth Maria Cecília Oliveira-Nunes, Weili Ma, Chenyu Mao, Brian S. Huo, Angela Rios Angulo, Gianfranco Landa Bianchi, Pulak Ray, and Qing Chen All author affiliations are listed at the end of the article Corresponding Author: Qing Chen, MD, PhD, Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 ([qing.chen@fccc.edu](qing.chen@fccc.edu)) . Abstract Background. Brain metastasis is the most ominous form of cancer relapse.There is urgent need to develop preclinical mouse models to study brain metastasis and new therapeutic strategies. Patient derived xenograft (PDX) models are clinically relevant mouse models.The brain stromal cells play critical roles on metastatic initiation and outgrowth. We have shown that PPARγ signaling in cancer cells is activated by astrocytes to increase brain metastatic outgrowth. Here, we aim to compare ectopic and orthotopic brain metastasis PDX models to address whether the unique brain microenvironment affects therapeutic efficacy of PPARγ antagonist. Methods. A collection of surgically resected brain metastasis tissues from cancer patients were used to generate PDX models. Ectopic and orthotopic brain metastasis PDX models were generated and characterized. The tumor growth was tracked in both PDX models when treated with PPARγ antagonist. Results. The growth rate of PDX tumors increased over passages in our ectopic PDX models and maintains in the orthotopic PDX models. Brain stromal cells were absent in the ectopic PDX tumors. Brain metastasis cancer cells sustained the PPARγ expression in both ectopic and orthotopic PDX tumors, atthe similar level as the original brain metastasis tissues. However, PPARγ antagonist only decreased tumor growth in the brain without affecting subcutaneous tumors. Conclusions. Our results show that PDX models are successfully generated from clinical brain metastasis tissues and maintain the molecular characteristics in the brain metastasis cancer cells. Moreover, our study indicates the importance of the brain microenvironment to the therapeutic response in brain metastasis. Key Points • Establishing ectopic and orthotopic brain metastasis PDX models. • Molecular characteristics are maintained in the cancer cells in PDX models. • The therapeutic effect of PPAR-gamma antagonist was dependent on the brain microenvironment in the orthotopic PDX models. Brain metastasis is a complex process that commonly occurs in lung, breast cancer and melanoma.1,2 Despite advances in technical and pharmacological approaches, current strategies have limited efficacy in brain metastases.3–6 As a consequence, the incidence of brain metastases has increased in recent years. Thus, brain metastasis is a significant problem in the clinic. It has been established that metastatic outgrowth at distal organs requires the complex interplay between cancer cells and the stromal cells,7–9 a process commonly referred to as “seed and soil hypothesis.”The “seed,” the invaded cancer cells, modifies the surrounding stromal cells.The “soil,” the microenvironment, decides the outgrowth of metastasis cancer cells. Due to the Received May 1, 2025; accepted November 9, 2025. © The Author(s) 2025. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by-nc/4.0/](licenses/by-nc/4.0/)), which permits non-commercial re-use,

FAQs

Why are patient-derived xenograft (PDX) models important for brain metastasis research?

PDX models are clinically relevant mouse models generated from patient tumor tissues. They help evaluate how therapeutic strategies perform in a setting that preserves tumor characteristics.

What was compared between the experimental groups in this study?

The study generated and characterized both ectopic and orthotopic brain metastasis PDX models. Tumor growth was tracked in both models under treatment with a PPARγ antagonist.

How did the PPARγ antagonist affect tumor growth in different microenvironments?

The PPARγ antagonist decreased tumor growth in the brain, while not affecting subcutaneous tumors. This indicates that therapeutic response depended on the brain microenvironment in orthotopic PDX models.

Sep 29, 2026

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