PT  - JOURNAL ARTICLE
AU  - Claudia C. Faria
AU  - Carlos Custódia
AU  - Rita Cascão
AU  - Eunice Paisana
AU  - Tânia Carvalho
AU  - Pedro Pereira
AU  - Rafael Roque
AU  - José Pimentel
AU  - José Miguéns
AU  - João T. Barata
TI  - Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers
AID  - 10.1101/2020.11.26.400036
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.11.26.400036
4099  - http://biorxiv.org/content/early/2020/11/27/2020.11.26.400036.short
4100  - http://biorxiv.org/content/early/2020/11/27/2020.11.26.400036.full
AB  - Purpose Dissemination 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 design We 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.Results In 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.Conclusions Patient-derived models of BMs recapitulate the biology of human metastatic disease and can be a valuable translational platform for precision medicine.TRANSLATIONAL RELEVANCE Subcutaneous 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.Competing Interest StatementThe authors have declared no competing interest.