Abstract 2844: Systems biology analysis of tumor and stromal genes in different metastatic microenvironments

Abstract

Abstract Metastasis is a multistage process that requires cancer cells to escape from the primary tumor, survive in the circulation, seed at distant sites and colonize these foreign tissue environments. Each of these processes involves rate-limiting steps that are influenced by stromal cells of the tumor microenvironment. Our goal is to dissect organ-site specific signatures of tumor-stroma interactions in metastasis. In this approach we devised an experimental and computational strategy to enable the simultaneous analysis of tumor and stromal genes in lesions from three distinct metastatic microenvironments. We took advantage of a recently developed system where organ-site specific metastatic variants were selected in vivo from a parental breast cancer cell line and home to the brain, the bone and the lung in xenografted animals. An important technological advance is the HuMu ProtIn (Protease/Inhibitor) array that was designed to distinguish between human (Hu) and mouse (Mu) gene expression. By using the HuMu ProtIn array we can determine whether differentially expressed proteases and endogenous protease inhibitors are of tumor (human) or stromal (mouse) origin. This allowed us to simultaneously capture the tumor and stromal contributions in intact tumors. After profiling of brain, bone and lung metastases at different stages of development we employed knock-down and knock-out strategies to experimentally validate the biological relevance of predicted candidate genes including the serine protease Htra1 and the cysteine protease cathepsin S. Cathepsin S represents an interesting example as the expression of tumor-derived cathepsin S decreases during the progression from early to late brain metastasis, whereas the expression of stromal-derived cathepsin S increases over time. Targeting either tumor- or stromal derived cathepsin S did not significantly prolong tumor-free survival, however the combined ablation of tumor- and stromal derived cathepsin S resulted in a dramatic impairment of brain metastasis formation. This study emphasizes the need for a better understanding of the complex reciprocal interactions between tumor cells and stromal cells with the ultimate goal to improve the predictive value of prognostic evaluation and to develop combination therapies that target the tumor along with its microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2844. doi:10.1158/1538-7445.AM2011-2844