The matrisome, a group of proteins constituting or interacting with the extracellular matrix (ECM), has garnered attention as a potent regulator of cancer progression. An increasing number of studies have focused on cancer matrisome utilizing diverse -omics approaches. Here, we present diverse patterns of matrisomal populations within cancer tissues, exploring recent -omics studies spanning different \'-omics\' levels (epigenomics, genomics, transcriptomics, and proteomics), as well as newly developed sequencing techniques such as single-cell RNA sequencing and spatial transcriptomics. Some matrisome genes showed uniform patterns of upregulated or downregulated expression across various cancers, while others displayed different expression patterns according to the cancer types. This matrisomal dysregulation in cancer was further examined according to their originating cell type and spatial location in the tumor tissue. Experimental studies were also collected to demonstrate the identified roles of matrisome genes during cancer progression. Interestingly, many studies on cancer matrisome have suggested matrisome genes as effective biomarkers in cancer research. Although the specific mechanisms and clinical applications of cancer matrisome have not yet been fully elucidated, recent techniques and analyses on cancer matrisomics have emphasized their biological importance in cancer progression and their clinical implications in deciding the efficacy of cancer treatment.

Proximity labeling (PL) has given researchers the tools to explore protein-protein interactions (PPIs) in living systems; however, most PL studies are performed on intracellular targets. We have adapted the original PL method to investigate PPIs within the extracellular compartment, which we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigated the interactome of the matrisome protein TIMP2. TIMPs are a family of multifunctional proteins that were initially defined by their ability to inhibit metalloproteinases, the major mediators of extracellular matrix (ECM) turnover. TIMP2 exhibits broad expression and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, such as TIMP2, during disease progression is essential for the development of ECM-targeted therapeutics. Using dual orientation fusion proteins of TIMP2 with BioID2/TurboID, we describe the TIMP2 proximal interactome (MassIVE MSV000095637). We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics, demonstrating the power of this technique versus classical PPI methods. We propose that screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.

Fibrosis is defined by the excessive accumulation of extracellular matrix (ECM) and constitutes a central pathophysiological process that underlies tissue dysfunction, across organs, in multiple chronic diseases and during aging. Myocardial fibrosis is a key contributor to dysfunction and failure in numerous diseases of the heart and is a strong predictor of poor clinical outcome and mortality. The excess structural and matricellular ECM proteins deposited by cardiac fibroblasts, is found between cardiomyocytes (interstitial fibrosis), in focal areas where cardiomyocytes have died (replacement fibrosis), and around vessels (perivascular fibrosis). Although myocardial fibrosis has important clinical prognostic value, access to cardiac tissue biopsies for histological evaluation is limited. Despite challenges with sensitivity and specificity, cardiac magnetic resonance imaging (CMR) is the most applicable diagnostic tool in the clinic, and the scientific community is currently actively searching for blood biomarkers reflecting myocardial fibrosis, to complement the imaging techniques. The lack of mechanistic insights into specific pro- and anti-fibrotic molecular pathways has hampered the development of effective treatments to prevent or reverse myocardial fibrosis. Development and implementation of anti-fibrotic therapies is expected to improve patient outcomes and is an urgent medical need. Here, we discuss the importance of the ECM in the heart, the central role of fibrosis in heart disease, and mechanistic pathways likely to impact clinical practice with regards to diagnostics of myocardial fibrosis, risk stratification of patients, and anti-fibrotic therapy.

The main component of human skin is a collagen-rich extracellular matrix (ECM), known as the matrisome. The matrisome is essential for maintaining the structural integrity and mechanical properties of the skin. Recently, we reported notable decreases in matrisome proteins in natural aging and photoaging human skin. This study aims to investigate the mRNA expression of the core matrisome proteins in human skin, comparing young versus aged and sun-protected versus sun-exposed skin by quantitative real-time PCR and immunostaining. Our findings reveal a notable decrease in core matrisome transcription in aged skin. The mRNA expression of the core matrisome, such as collagen 1A1 (COL1A1), decorin, and dermatopontin, is significantly reduced in aged skin compared to its young skin. Yet, the majority of collagen mRNA expression levels of aged sun-exposed skin are similar to those found in young sun-exposed skin. This discrepancy is primarily attributable to a substantial decrease in collagen transcription in young sun-exposed skin, suggesting early molecular changes in matrisome transcription due to sun exposure, which preceded the emergence of clinical signs of photoaging. These findings shed light on the mRNA transcript profile of major matrisome proteins and their alterations in naturally aged and photoaged human skin, offering valuable insights into skin matrisome biology.

The extracellular matrix (ECM) comprises macromolecules that shape a complex three-dimensional network. Filling the intercellular space and playing a crucial role in the structure and function of tissues, ECM regulates essential cellular processes such as adhesion, differentiation, and cell signaling. In the human adrenal gland, composed of cortex and medulla surrounded by a capsule, the ECM has not yet been directly described, although its impact on the processes of proliferation and steroidogenesis of the adrenal cortex is recognized. This study analyzes the ECM of the adult human adrenal cortex, which was separated into outer fraction (OF) and inner fraction (IF), by comparing their proteomic profiles. The study discusses the composition, spatial distribution, and relevance of differentially expressed ECM signatures of the adrenal cortex matrisome on adrenal structure and function. The findings were validated through database analysis (cross-validation), histochemical, and immunohistochemical approaches. A total of 121 ECM proteins were identified and categorized into glycoproteins, collagens, ECM regulators, proteoglycans, ECM-affiliated proteins, and secreted factors. Thirty-one ECM proteins were identified only in OF, nine only in IF, and 81 were identified in common with both fractions. Additionally, 106 ECM proteins were reported in the Human matrisome DB 2.0, and the proteins differentially expressed in OF and IF, were identified. This study provides significant insights into the composition and regulation of the ECM in the human adrenal cortex, shedding light on the adrenal microenvironment and its role in the functioning, maintenance, and renewal of the adrenal gland.

Radiotherapy of prostate cancer (PC) can lead to the acquisition of radioresistance through molecular mechanisms that involve, in part, cell adhesion-mediated signaling. To define these mechanisms, we employed a DU145 PC model to conduct a comparative mass spectrometry-based proteomic analysis of the purified integrin nexus, i.e., the cell-matrix junction where integrins bridge assembled extracellular matrix (matrisome components) to adhesion signaling complexes (adhesome components). When parental and radioresistant cells were compared, the expression of integrins was not changed, but cell radioresistance was associated with extensive matrix remodeling and changes in the complement of adhesion signaling proteins. Out of 72 proteins differentially expressed in the parental and radioresistant cells, four proteins were selected for functional validation based on their correlation with biochemical recurrence-free survival. Perlecan/heparan sulfate proteoglycan 2 (HSPG2) and lysyl-like oxidase-like 2 (LOXL2) were upregulated, while sushi repeat-containing protein X-linked (SRPX) and laminin subunit beta 3 (LAMB3) were downregulated in radioresistant DU145 cells. Knockdown of perlecan/HSPG2 sensitized radioresistant DU145 RR cells to irradiation while the sensitivity of DU145 parental cells did not change, indicating a potential role for perlecan/HSPG2 and its associated proteins in suppressing tumor radioresistance. Validation in androgen-sensitive parental and radioresistant LNCaP cells further supported perlecan/HSPG2 as a regulator of cell radiosensitivity. These findings extend our understanding of the interplay between extracellular matrix remodeling and PC radioresistance and signpost perlecan/HSPG2 as a potential therapeutic target and biomarker for PC.

The extracellular matrix (ECM) is a complex meshwork comprising over 100 proteins. It serves as an adhesive substrate for cells and, hence, plays critical roles in health and disease. We have recently identified a novel ECM protein, SNED1, and have found that it is required for neural crest cell migration and craniofacial morphogenesis during development and in breast cancer, where it is necessary for the metastatic dissemination of tumor cells. Interestingly, both processes involve the dynamic remodeling of cell-ECM adhesions via cell surface receptors. Sequence analysis revealed that SNED1 contains two amino acid motifs, RGD and LDV, known to bind integrins, the largest class of ECM receptors. We thus sought to investigate the role of SNED1 in cell adhesion. Here, we report that SNED1 mediates breast cancer and neural crest cell adhesion via its RGD motif. We further demonstrate that cell adhesion to SNED1 is mediated by α5β1integrin. These findings are a first step toward identifying the signaling pathways activated downstream of the SNED1-integrin interactions guiding craniofacial morphogenesis and breast cancer metastasis.

UNASSIGNED: African Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimer\'s disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD.
UNASSIGNED: Untargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy.
UNASSIGNED: A plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94).
UNASSIGNED: This study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood-brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer\'s disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. Histone deacetylases (HDACs) inhibitors are epigenetic regulators that can induce acetylation of histones and induce open chromatin conformation, promoting gene expression by enhancing the binding of DNA with transcription factors. We investigated how HDAC inhibition influences the barrier integrity using immortalized human endothelial cells (HCMEC/D3) and the human induced pluripotent stem cell (iPSC)-derived brain vascular endothelial cells. The endothelial cells were treated with or without a novel compound named W2A-16. W2A-16 not only activates Wnt/β-catenin signaling but also functions as a class I HDAC inhibitor. We demonstrated that the administration with W2A-16 sustained barrier properties of the monolayer of endothelial cells, as evidenced by increased trans-endothelial electrical resistance (TEER). The BBB-related genes and protein expression were also increased compared with non-treated controls. Analysis of transcript profiles through RNA-sequencing in hCMEC/D3 cells indicated that W2A-16 potentially enhances BBB integrity by influencing genes associated with the regulation of the extracellular microenvironment. These findings collectively propose that the HDAC inhibition by W2A-16 plays a facilitating role in the formation of the BBB. Pharmacological approaches to inhibit HDAC may be a potential therapeutic strategy to boost and/or restore BBB integrity.

UNASSIGNED: Human extracellular matrix (ECM) exhibits complex protein composition and architecture depending on tissue and disease state, which remains challenging to reverse engineer. One promising approach is based on cell-secreted ECM from primary human fibroblasts that can be decellularized into acellular biomaterials. However, fibroblasts cultured on rigid culture plastic or biomaterial scaffolds can experience aberrant mechanical cues that perturb the biochemical, mechanical, and the efficiency of ECM production.
UNASSIGNED: Here, we demonstrate a method for preparing decellularized ECM using primary human fibroblasts with tissue and disease-specific features with two case studies: (1) cardiac fibroblasts; (2) lung fibroblasts from healthy or diseased donors. Cells aggregate into engineered microtissues in low adhesion microwells that deposited ECM and can be decellularized. We systematically investigate microtissue morphology, matrix architecture, and mechanical properties, along with transcriptomic and proteomic analysis.
UNASSIGNED: Microtissues exhibited tissue-specific gene expression and proteomics profiling, with ECM complexity similar to native tissues. Healthy lung microtissues exhibited web-like fibrillar collagen compared to dense patches in healthy heart microtissues. Diseased lung exhibited more disrupted collagen architecture than healthy. Decellularized microtissues had tissue-specific mechanical stiffness that was physiologically relevant. Importantly, decellularized microtissues supported viability and proliferation of human cells.
UNASSIGNED: We show that engineered microtissues of primary human fibroblasts seeded in low-adhesion microwells can be decellularized to produce human, tissue and disease-specific ECM. This approach should be widely applicable for generating personalized matrix that recapitulate tissues and disease states, relevant for culturing patient cells ex vivo as well as implantation for therapeutic treatments.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12195-024-00809-y.