Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers

Abstract

PurposeDissemination of cancer cells from primary tumors to the brain is observed in the great majority of cancer patients, contributing to increased morbidity and being the main cause of death. Most mechanistic and preclinical studies have relied on aggressive cancer cell lines, which fail to represent tumor heterogeneity and are unsuitable to validate therapies due to fast cancer progression in vivo.Experimental designWe established a unique library of subcutaneous and intracardiac patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumor origins. Cancer progression in mice was compared to the matched patient clinical outcome, metastatic dissemination pattern and histopathological features. Preclinical studies with FDA approved drugs were performed.ResultsIn vivo tumor formation of flank-implanted BMs correlated with patients’ poor survival and serial passaging increased tumor aggressiveness. Subcutaneous xenografts originated spontaneous metastases in 61% of the cases, including in the leptomeningeal space (21%). The intracardiac model increased the tropism to the brain and leptomeninges (46%). Strikingly, 62% of intracardiac PDXs shared metastatic sites with the donor patients, including the primary cancer organ and the central nervous system (CNS). Of therapeutic relevance, PDX-derived cultures and corresponding mouse xenografts can be effectively treated with targeted anticancer drugs.ConclusionsPatient-derived models of BMs recapitulate the biology of human metastatic disease and can be a valuable translational platform for precision medicine.TRANSLATIONAL RELEVANCESubcutaneous and intracardiac mouse xenografts of human brain metastases exhibit a spontaneous dissemination pattern that resembles patients’ metastatic disease. The preclinical testing of targeted anticancer drugs using patient-derived cultures and patient-derived xenografts of brain metastasis showed an effective therapeutic response. These translational models represent an outstanding tool to advance the understanding of the biology of brain metastases and to foster the rapid discovery of novel therapeutics.

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“…Another group has recently established patient‐derived xenografts from resected parenchymal brain tumors that spontaneously metastasize to the leptomeningeal space when injected subcutaneously in 21% of the cases (Faria et al, 2020). Going a step further, Law et al (2022) have developed in vitro and in vivo models of LMD from patient‐derived cerebrospinal fluid circulating tumor cells (PD‐CSF‐CTCs).…”

“…This model takes more time to develop but has the advantage of capturing a more representative colonization process of cells seeding to the CSF. However, even in this model, the process of intracardiac injection skips several steps in the metastatic process.Another group has recently established patient-derived xenografts from resected parenchymal brain tumors that spontaneously metastasize to the leptomeningeal space when injected subcutaneously in 21% of the cases(Faria et al, 2020). Going a step further,Law et al (2022) have developed in vitro and in vivo models of LMD from patient-derived cerebrospinal fluid circulating tumor cells (PD-CSF-CTCs).…”