Advances on the roles of tenascin-C in cancer.

The roles of the extracellular matrix molecule tenascin-C (TNC) in health and disease have been extensively reviewed since its discovery over 40 years ago. Here, we will describe recent insights into the roles of TNC in tumorigenesis, angiogenesis, immunity and metastasis. In addition to high levels of expression in tumors, and during chronic inflammation, and bacterial and viral infection, TNC is also expressed in lymphoid organs. This supports potential roles for TNC in immunity control. Advances using murine models with engineered TNC levels were instrumental in the discovery of important functions of TNC as a danger-associated molecular pattern (DAMP) molecule in tissue repair and revealed multiple TNC actions in tumor progression. TNC acts through distinct mechanisms on many different cell types with immune cells coming into focus as important targets of TNC in cancer. We will describe how this knowledge could be exploited for cancer disease management, in particular for immune (checkpoint) therapies.

The alternative matrisome: Alternative splicing of ECM proteins in development, homeostasis and tumor progression.

The extracellular matrix (ECM) is a fundamental component of the tissue of multicellular organisms that is comprised of an intricate network of multidomain proteins and associated factors, collectively known as the matrisome. The ECM creates a biophysical environment that regulates essential cellular processes such as adhesion, proliferation and migration and impacts cell fate decisions. The composition of the ECM varies across organs, developmental stages and diseases. Interestingly, most ECM genes generate transcripts that undergo extensive alternative splicing events, producing multiple protein variants from one gene thus enhancing ECM complexity and impacting matrix architecture. Extensive studies over the past several decades have linked ECM remodeling and expression of alternatively spliced ECM isoforms to cancer, and reprogramming of the alternative splicing patterns in cells has recently been proposed as a new hallmark of tumor progression. Indeed, tumor-associated alternative splicing occurs in both malignant and non-malignant cells of the tumor environment and growing evidence suggests that expression of specific ECM splicing variants could be a key step for stromal activation. In this review, we present a general overview of alternative splicing mechanisms, featuring examples of ECM components. The importance of ECM variant expression during essential physiological processes, such as tissue organization and embryonic development is discussed as well as the dysregulation of alternative splicing in cancer. The overall aim of this review is to address the complexity of the ECM by highlighting the importance of the yet-to-be-fully-characterized "alternative" matrisome in physiological and pathological states such as cancer.

Analysis of extracellular matrix network dynamics in cancer using the MatriNet database.

The extracellular matrix (ECM) is a three-dimensional network of proteins of diverse nature, whose interactions are essential to provide tissues with the correct mechanical and biochemical cues they need for proper development and homeostasis. Changes in the quantity of extracellular matrix (ECM) components and their balance within the tumor microenvironment (TME) accompany and fuel all steps of tumor development, growth and metastasis, and a deeper and more systematic understanding of these processes is fundamental for the development of future therapeutic approaches. The wealth of "big data" from numerous sources has enabled gigantic steps forward in the comprehension of the oncogenic process, also impacting on our understanding of ECM changes in the TME. Most of the available studies, however, have not considered the network nature of ECM and the possibility that changes in the quantity of components might be regulated (co-occur) in cancer and significantly "rebound" on the whole network through its connections, fundamentally altering the matrix interactome. To facilitate the exploration of these network-scale effects we have implemented MatriNet (www.matrinet.org), a database enabling the study of structural changes in ECM network architectures as a function of their protein-protein interaction strengths across 20 different tumor types. The use of MatriNet is intuitive and offers new insights into tumor-specific as well as pan-cancer features of ECM networks, facilitating the identification of similarities and differences between cancers as well as the visualization of single-tumor events and the prioritization of ECM targets for further experimental investigations.