The extracellular matrix is a fundamental, core component of all tissues and organs, and is essential for the existence of multicellular organisms. From the earliest stages of organism development until death, it regulates and fine-tunes every cellular process in the body. In cancer, the extracellular matrix is altered at the biochemical, biomechanical, architectural and topographical levels, and recent years have seen an exponential increase in the study and recognition of the importance of the matrix in solid tumours. Coupled with the advancement of new technologies to study various elements of the matrix and cell-matrix interactions, we are also beginning to see the deployment of matrix-centric, stromal targeting cancer therapies. This Review touches on many of the facets of matrix biology in solid cancers, including breast, pancreatic and lung cancer, with the aim of highlighting some of the emerging interactions of the matrix and influences that the matrix has on tumour onset, progression and metastatic dissemination, before summarizing the ongoing work in the field aimed at developing therapies to co-target the matrix in cancer and cancer metastasis.

The matrix in cancer.

Mechanical forces shape cells and tissues during development and adult homeostasis. In addition, they also signal to cells via mechanotransduction pathways to control cell proliferation, differentiation and death. These processes require metabolism of nutrients for both energy generation and biosynthesis of macromolecules. However, how cellular mechanics and metabolism are connected is still poorly understood. Here, we discuss recent evidence indicating how the mechanical cues exerted by the extracellular matrix (ECM), cell-ECM and cell-cell adhesion complexes influence metabolic pathways. Moreover, we explore the energy and metabolic requirements associated with cell mechanics and ECM remodelling, implicating a reciprocal crosstalk between cell mechanics and metabolism.

Crosstalk between mechanotransduction and metabolism

The extracellular matrix (ECM) is a complex and dynamic meshwork of cross-linked proteins that supports cell polarization and functions and tissue organization and homeostasis. Over the past few decades, mass-spectrometry-based proteomics has emerged as the method of choice to characterize the composition of the ECM of normal and diseased tissues. Here, we present a new release of MatrisomeDB, a searchable collection of curated proteomic data from 17 studies on the ECM of 15 different normal tissue types, six cancer types (different grades of breast cancers, colorectal cancer, melanoma, and insulinoma) and other diseases including vascular defects and lung and liver fibroses. MatrisomeDB (http://www.pepchem.org/matrisomedb) was built by retrieving raw mass spectrometry data files and reprocessing them using the same search parameters and criteria to allow for a more direct comparison between the different studies. The present release of MatrisomeDB includes 847 human and 791 mouse ECM proteoforms and over 350 000 human and 600 000 mouse ECM-derived peptide-to-spectrum matches. For each query, a hierarchically-clustered tissue distribution map, a peptide coverage map, and a list of post-translational modifications identified, are generated. MatrisomeDB is the most complete collection of ECM proteomic data to date and allows the building of a comprehensive ECM atlas.

/pdf/matrisomedb-the-ecm-protein-knowledge-database-2xqa66smna.pdf

MatrisomeDB: the ECM-protein knowledge database.

SARS-CoV-2 infection poses a major threat to the lungs and multiple other organs, occasionally causing death. Until effective vaccines are developed to curb the pandemic, it is paramount to define the mechanisms and develop protective therapies to prevent organ dysfunction in patients with COVID-19. Individuals that develop severe manifestations have signs of dysregulated innate and adaptive immune responses. Emerging evidence implicates neutrophils and the disbalance between neutrophil extracellular trap (NET) formation and degradation plays a central role in the pathophysiology of inflammation, coagulopathy, organ damage, and immunothrombosis that characterize severe cases of COVID-19. Here, we discuss the evidence supporting a role for NETs in COVID-19 manifestations and present putative mechanisms, by which NETs promote tissue injury and immunothrombosis. We present therapeutic strategies, which have been successful in the treatment of immunο-inflammatory disorders and which target dysregulated NET formation or degradation, as potential approaches that may benefit patients with severe COVID-19.

/pdf/patients-with-covid-19-in-the-dark-nets-of-neutrophils-3kv4hbuj18.pdf

Patients with COVID-19: in the dark-NETs of neutrophils.

In 1971, Gabbiani and co-workers discovered and characterized the "modification of fibroblasts into cells which are capable of an active spasm" (contraction) in rat wound granulation tissue and, accordingly, named these cells 'myofibroblasts'. Now, myofibroblasts are not only recognized for their physiological role in tissue repair but also as cells that are key in promoting the development of fibrosis in all organs. In this Cell Science at a Glance and the accompanying poster, we provide an overview of the current understanding of central aspects of myofibroblast biology, such as their definition, activation from different precursors, the involved signaling pathways and most widely used models to study their function. Myofibroblasts will be placed into context with their extracellular matrix and with other cell types communicating in the fibrotic environment. Furthermore, the challenges and strategies to target myofibroblasts in anti-fibrotic therapies are summarized to emphasize their crucial role in disease progression.

/pdf/the-myofibroblast-at-a-glance-4p4hawznry.pdf

The myofibroblast at a glance.

Citrullination of fibronectin alters integrin clustering and focal adhesion stability promoting stromal cell invasion

The glycosylphosphatidylinositol (GPI) anchored glycoprotein Thy-1 has been prevalently expressed on the surface of various cell types. The biological function of Thy-1 ranges from T cell activation, cell adhesion, neurite growth, differentiation, metastasis and fibrogenesis and has been extensively reviewed elsewhere. However, current discoveries implicate Thy-1 also functions as a key mechanotransduction mediator. In this review, we will be focusing on the role of Thy-1 in translating extracellular mechanic cues into intracellular biological cascades. The mechanotransduction capability of Thy-1 relies on trans and cis interaction between Thy-1 and RGD-binding integrins; and will be discussed in depth in the review.

/pdf/thy-1-in-integrin-mediated-mechanotransduction-pebxs7i46h.pdf

Thy-1 in Integrin Mediated Mechanotransduction.

Aberrant deposition of the extracellular matrix (ECM) causes fibrosis and leads to ECM stiffening. This fibrotic ECM provides biological and biophysical stimulations to alter cell activity and drive progression of fibrosis. As an emerging discipline, mechanobiology aims to access the impact of both these cues on cell behavior and relates the reciprocity of mechanical and biological interactions; it incorporates concepts from different fields, like biology and physics, to help study the mechanical and biological facets of fibrosis extensively. A useful experimental platform in mechanobiology is decellularized ECM (dECM), which mimics the native microenvironment more accurately than standard 2D culture techniques as its composition includes similar ECM protein components and stiffness. dECM, therefore, generates more reliable results that better recapitulate in vivo fibrosis.

Decellularized Extracellular Matrix (ECM) as a Model to Study Fibrotic ECM Mechanobiology.

Biophysical cues stemming from the extracellular environment are rapidly transduced into discernible chemical messages (mechanotransduction) that direct cellular activities-placing the extracellular matrix (ECM) as a potent regulator of cell behavior. Dynamic reciprocity between the cell and its associated matrix is essential to the maintenance of tissue homeostasis and dysregulation of both ECM mechanical signaling, via pathological ECM turnover, and internal mechanotransduction pathways contribute to disease progression. This review covers the current understandings of the key modes of signaling used by both the cell and ECM to coregulate one another. By taking an outside-in approach, the inherent complexities and regulatory processes at each level of signaling (ECM, plasma membrane, focal adhesion, and cytoplasm) are captured to give a comprehensive picture of the internal and external mechanoregulatory environment. Specific emphasis is placed on the focal adhesion complex which acts as a central hub of mechanical signaling, regulating cell spreading, migration, proliferation, and differentiation. In addition, a wealth of available knowledge on mechanotransduction is curated to generate an integrated signaling network encompassing the central components of the focal adhesion, cytoplasm and nucleus that act in concert to promote durotaxis, proliferation, and differentiation in a stiffness-dependent manner.

Feeling Things Out: Bidirectional Signaling of the Cell-ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation.

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Papers

Citrullination of fibronectin alters integrin clustering and focal adhesion stability promoting stromal cell invasion

Thy-1 in Integrin Mediated Mechanotransduction.

Decellularized Extracellular Matrix (ECM) as a Model to Study Fibrotic ECM Mechanobiology.

Feeling Things Out: Bidirectional Signaling of the Cell-ECM Interface, Implications in the Mechanobiology of Cell Spreading, Migration, Proliferation, and Differentiation.