Abstract
Abstract Although advances have been made in the treatment of localized breast cancer, there has been less progress in the treatment of advanced metastatic disease. This disease is an oncoming therapeutic challenge for breast cancer since it is always fatal. Conventional therapies may fail to target cancer stem cells (CSC). Metastatic breast cancer may thus benefit from current intensive research in the CSC field. Several studies suggest that CSCs are the only cancer cells responsible for metastasis formation. CSCs may have the ability to disseminate in blood circulation as circulating tumor cells (CTCs) and to colonize new sites. To better understand the biological processes that link CSCs and metastasis, we have generated a xenobank of 50 patient-derived xenografts (PDXs) of primary tumors grafted in the humanized mammary fat pad of immunodeficient mice. These models reflect the heterogeneity of primary tumors both at molecular and cellular level. Using a lentiviral vector, we infected our PDXs to obtain GFP-luciferase-positive models designed to monitor metastasis development from the orthotopic site. To mimick the patient therapeutic management, metastasis formation is monitored during tumor growth but also after tumor surgical removal. Metastases are collected and analyzed for histology and phenotype. The different metastatic patterns are correlated with the mutational profile of PDX. CTCs are also monitored at different time of the metastatic process using a specific filter (ISET) for cell characterization and phenotype. PDXs can be classified in tumor groups with similar metastatic tropisms. To depict the role of CSC from primary tumors in the tropism of their metastases, we collected and genomic profiled the ALDEFLUOR-positive CSCs in orthotopic tumors from different models with distinct metastatic pattern. These different PDX models lead to a better understanding of the role of breast CSCs in metastasis formation from CTCs to well-constituted metastasis and their study may identify targets able to design future therapeutic strategies. Citation Format: Christophe Ginestier, Danae Lartigue, Olivier Cabaud, Aurelie Malzac, Julien Wicinski, Emmanuelle Josselin, Pascal Finetti, Jose Adelaide, Francois Bertucci, Max Chaffanet, Daniel Birnbaum, Emmanuelle Charafe-Jauffret. Patient-derived xenograft (PDX) models to study the role of breast cancer stem cells in metastasis formation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3020. doi:10.1158/1538-7445.AM2014-3020
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