Abstract 5004: Profiling the extracellular matrix landscape of tumor microenvironments using proteomics

Abstract

Abstract "Your cancer has spread" remains for most cancer patients synonymous with a death sentence. Indeed, the majority of cancer deaths are due to metastases: the dissemination of tumor cells from a primary tumor to distant vital organs. As of today, we do not have efficient treatments to stabilize or cure most metastatic cancers, and for patients diagnosed early, i.e., before metastases are detectable, we do not have reliable markers to predict whether their tumors will remain indolent or will become deadly. Tumor progression critically depends on a locally permissive microenvironment, including a unique tumor-associated extracellular matrix (ECM). The ECM is a complex meshwork of proteins providing architectural support to cells and conferring biomechanical properties to tissues. ECM-derived biochemical signals transduced by cell-surface receptors, such as the integrins, regulate cellular functions such as proliferation and survival, adhesion, and migration, all essential for metastasis. Importantly, clinicians have observed that more aggressive tumors present a higher ECM content. Thus, to fully understand how tumors progress and disseminate, it is essential to study the tumor ECM. To do so, we have developed a pipeline combining bioinformatics and proteomics to comprehensively characterize the ECM composition, or "matrisome," of tissues and tumors. Using this pipeline, we demonstrated that the composition of the ECM varies i) between normal tissues and tumors, ii) between poorly and highly metastatic primary tumors, and iii) between primary tumors and derived metastases. Here we present for the first time "The Tumor ECM Atlas," a compendium of ECM proteins identified by proteomics in the microenvironment of 10+ types of primary tumors and derived metastases, including breast, colorectal and lung cancers, insulinomas and multiple myelomas, which revealed the presence of a unique subset of cancer-specific and cancer type-specific ECM proteins. We believe that this atlas is a powerful tool to formulate novel hypotheses on the roles of the ECM in tumor progression and metastasis. In addition, we propose that the ECM is an underexplored reservoir of potential diagnostic and prognostic markers and therapeutic targets, and that its exploration using proteomics will pave the way for the development of novel approaches to better care for cancer patients. Citation Format: Alexandra Naba, Karl R. Clauser, Steven A. Carr, Richard O. Hynes. Profiling the extracellular matrix landscape of tumor microenvironments using proteomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5004.