Tissue engineering is a growing field with multidisciplinary players in cell biology, engineering, and medicine, aiming to maintain, restore, or enhance functions of tissues and organs. The extracellular matrix (ECM) plays fundamental roles in tissue development, maintenance, and repair, providing not only structural support, but also critical biochemical and biomechanical cues that regulate cell behavior and signaling. Although its specific composition varies across different tissue types and developmental stages, matrix molecules influence various cell functional properties in every tissue. Given the importance of ECM in morphogenesis, tissue homeostasis, and regeneration, ECM-based bioscaffolds, developed through tissue engineering approaches, have emerged as pivotal tools for recreating the native cellular microenvironment. The aim of this study is to present the main categories of these scaffolds (i.e., natural, synthetic, and hybrid), major fabrication techniques (i.e., tissue decellularization and multidimensional bioprinting), while highlighting the advantages and disadvantages of each category, focusing on biological activity and mechanical performance. Scaffold properties, such as mechanical strength, elasticity, biocompatibility, and biodegradability are essential to their function and integration into host tissues. Applications of ECM-based bioscaffolds span a range of engineering and regenerative strategies, including cartilage, bone, cardiac tissue engineering, and skin wound healing. Despite promising advances, challenges remain in standardization, scalability, and immune response modulation, with future directions directed towards improving ECM-mimetic platforms.

Traditional 2D cell culture models present significant limitations in replicating the intricate architecture and microenvironment of in vivo solid tumors, which are essential for accurately studying cancer initiation, growth, progression, and metastasis. This underscores the need for the development of advanced preclinical models to accelerate research outcomes. Emerging 3D cell culture systems, particularly spheroid models, provide a more realistic representation of solid tumor properties by capturing the complex interactions occurring within the tumor microenvironment, including the extracellular matrix dynamics that influence cancer progression. Among solid tumors, breast cancer remains the most frequently diagnosed cancer among women globally and a leading cause of cancer-related mortality. Here we emphasize the value of breast cancer cell-derived spheroids in revealing differential molecular characteristics and understanding cancer cell properties during the early stages of invasion into adjacent tissues. Conclusively, this study underscores the urgent need to adopt 3D cell culture platforms, given their significant contributions to advanced cancer research and pharmaceutical targeting. This may well offer a transformative approach for preclinical studies and enhance our ability to test therapeutic efficiency in conditions that closely mimic the growth and progression of in vivo solid tumors.

Cancer remains a significant global health concern. Breast cancer is a multifaceted and prevalent disease influenced by several factors, among which estrogen receptors (ERs) and the extracellular matrix (ECM) play pivotal roles. ERs, encompassing ERα and ERβ, exert significant diversity on tumor behavior, cell signaling, invasion, and metastatic potential, thus guiding breast cancer prognosis. Understanding the multifunctional connections between ERs and ECM that mediate the dynamics of tumor microenvironment is vital for unraveling the complexity of breast cancer pathobiology and identifying novel therapeutic targets. This critical review delves into the intricate nature of ERs, emphasizing their structural isoforms and the consequential impact on breast cancer outcomes. A detailed examination of ER‐mediated cell signaling pathways reveals how differential expression of ERα and ERβ isoforms influence breast cancer cell behavior. The functional ERs‐matrix interactions emerge as a pivotal factor in modulating epigenetic mechanisms of breast cancer cells, orchestrating changes in cellular phenotype and expression patterns of matrix modulators. Specifically, ERα isoforms are shown to regulate ECM signaling cascades, while the effects of ECM components on ERα activity highlight a bidirectional regulatory axis. The diversity of ERβ isoforms is also highlighted, illustrating their distinct contribution to ECM‐mediated cellular responses. This review underscores the complex interplay between ERα/β isoforms and the ECM, shedding light onto the potential therapeutic strategies targeting these interactions to improve breast cancer management.

Cell–cell communication is essential for the regulated exchange of information between cells, coordinating critical cellular processes under physiological and pathological conditions. The extracellular matrix (ECM) is a complex three‐dimensional (3D) intercellular macromolecular network that provides structural support to tissues, while actively modulating cellular functions and responses. ECM‐mediated intercellular communication is a key player in both homeostasis and disease development. Particularly in cancer, ECM reorganization drives tumor development and progression, shaping dynamic interactions within the tumor microenvironment (TME). In this review, we present and discuss two principal mechanisms of matrix‐mediated cell–cell communication in both physiological and cancerous contexts. First, we explore the impact of ECM biomechanical properties in mechanical sensing and communication, which govern key aspects of cell signaling, adhesion, and migration across normal and malignant tissues. Second, we discuss the role of the ECM in facilitating cell–cell communication through the controlled release and navigation of extracellular vesicles (EVs). EVs carry, among other constituents, proteins, enzymes, microRNAs (miRNAs), and signaling molecules that relay information to nearby or distant cells, modulating the initiation of metastasis and pre‐metastatic niche formation. Conclusively, in this review, we highlight the critical role of targeting ECM dynamics in cell–cell communication under physiological processes and during cancer progression. Targeted therapies that modulate ECM components and interactions with cells hold promise for future treatment approaches.

The onset, development, and progression of cancer are greatly influenced by the microenvironmental cues originating from diverse elements within the tumor niche. Extracellular matrix (ECM), the complex and dynamic macromolecular three-dimensional network (3-D), governs cell functionality and plays key roles in tumor growth and spreading. This article highlights the significance of ECM-based bioscaffolds in providing a relevant microenvironment not only for studying tumor behavior and drug efficacy but also for narrowing the gap between translational cancer research and targeted cancer treatment. The development of novel and user-friendly platforms that resemble the human tumor microenvironment in early and advanced cancer stages, may help to predict treatment response, thus facilitating the development and testing of new drugs, bridging the gap between in vitro and in vivo models. In addition, we present innovative strategies leveraging ECM bioscaffolds for personalized cancer treatment, including drug delivery systems and tissue engineering approaches. Specific case studies as well as ethical concerns related to the use of ECM bioscaffolds in research and therapy are also presented and critically discussed. By elucidating the intricate interplay between ECM and cancer biology, this article underscores the potential of ECM bioscaffolds as novel platforms for shaping future therapeutic interventions and advancing precision oncology.

Breast cancer invasion and subsequent metastasis to distant tissues occur when cancer cells lose cell–cell contact, develop a migrating phenotype, and invade the basement membrane (BM) and the extracellular matrix (ECM) to penetrate blood and lymphatic vessels. The identification of the mechanisms which induce the development from a ductal carcinoma in situ (DCIS) to a minimally invasive breast carcinoma (MIBC) is an emerging area of research in understanding tumor invasion and metastatic potential. To investigate the progression from DCIS to MIBC, we analyzed peritumoral collagen architecture using correlative scanning electron microscopy (SEM) on histological sections from human biopsies. In DCIS, the peritumoral collagen organizes into concentric lamellae (‘circular fibers’) parallel to the ducts. Within each lamella, type I collagen fibrils align in parallel, while neighboring lamellae show orthogonal fiber orientation. The concentric lamellar arrangement of collagen may physically constrain cancer cell migration, explaining the lack of visible tumor cell invasion into the peritumoral ECM in DCIS. A lamellar dissociation or the development of small inter fiber gaps allowed isolated breast cancer cell invasion and exosomes infiltration in the DCIS microenvironment. The radially arranged fibers observed in the peri-tumoral microenvironment of MIBC biopsies develop from a bending of the circular fibers of DCIS and drive a collective cancer cell invasion associated with an intense immune cell infiltrate. Type I collagen fibrils represent the peri-tumoral nano-environment which can play a mechanical role in regulating the development from DCIS to MIBC. Collectively, it is plausible to suggest that the ECM effectors implicated in breast cancer progression released by the interplay between cancer, stromal, and/or immune cells, and degrading inter fiber/fibril hydrophilic ECM components of the peritumoral ECM, may serve as key players in promoting the dissociation of the concentric collagen lamellae.