Ten Years of Extracellular Matrix Proteomics: Accomplishments, Challenges, and Future Perspectives

The extracellular matrix (ECM) is a complex assembly of hundreds of proteins forming the architectural scaffold of multicellular organisms. In addition to its structural role, the ECM conveys signals orchestrating cellular phenotypes. Alterations of ECM composition, abun-dance, structure, or mechanics have been linked to diseases and disorders affecting all physiological sys-tems, including fibrosis and cancer. Deciphering the protein composition of the ECM and how it changes in pathophysiological contexts is thus the first step toward understanding the roles of the ECM in health and dis-ease and toward the development of therapeutic stra-tegies to correct disease-causing ECM alterations. Potentially, the ECM also represents a vast, yet un-tapped reservoir of disease biomarkers. ECM proteins are characterized by unique biochemical properties that have hindered their study: they are large, heavily and uniquely posttranslationally modified, and highly insol-uble. Overcoming these challenges, we and others have devised mass-spectrometry-based proteomic ap-proaches to define the ECM composition, or "matri-some," of tissues. This first part of this review provides a historical overview of ECM proteomics research and presents the latest advances that now allow the profiling of the ECM of healthy and diseased tissues. The second part highlights recent examples illustrating how ECM proteomics has emerged as a powerful discovery pipe-line to identify prognostic cancer biomarkers. The third part discusses remaining challenges limiting our ability to translate findings to clinical application and proposes approaches to overcome them. Lastly, the review in-troduces readers to resources available to facilitate the interpretation of ECM proteomics datasets. The ECM was once thought to be impenetrable. Mass spectrometry-based proteomics has proven to be a powerful tool to decode the ECM. In light of the progress made over the past decade, there are reasons to believe that the in-depth exploration of the matrisome is within reach and that we may soon witness the first trans-lational application of ECM proteomics.