The global cancer burden has risen, with cases growing to 1.44 million between 2006 to 2016 [1]. This incidence is estimated to rise to 40% by 2040, owing to increasing total life expectancy [2]. Patient prognosis worsens due to delayed detection, misdiagnosis, inefficacious therapeutic intervention, and the spread of disease or ‘metastasis’. Metastasis is a complex cascade of events that results in some tumor cells breaking away from the primary site and traveling to distant organs to form secondary tumors [3,4]. This occurs in sequential steps: (1) invasion of cells in their surrounding tissue environment, (2) intravasation into existing or newly formed blood vessels, (3) cell survival from circulation, (4) extravasation from the blood vessel wall, (5) infiltration and colonization at the secondary target tissue site. The five-year average survival rate for commonly occurring solid tumors (breast, lung, colorectal, liver) at the late stage (stage 4) is approximately 13% and is notoriously difficult to treat as the tumors are no longer localized [5]. The first step of this cascade, invasion, begins as a result of tumor cells dynamically interacting with several exogenous chemical and mechanical stimuli fuelled by the physical changes in the ECM and interaction with surrounding stromal cells. While a plethora of evidence has appreciated chemical cues as the key drivers of tumor progression, there is now a surging interest in the physical signals and how their alterations may guide tumor invasion. Dissecting each biophysical aspect and decoding their impact on intracellular mechanotransductive machinery can help develop and translate a new class of drugs that target the abnormal ECM and its molecular drivers of tumor progression. Limited consistent evidence makes it challenging to guide these actions.

During the last decade, mechanobiology has gained recognition as a field that brought about new technologies, experiments, and findings focusing on abnormal tumor ECM and its physical forces. Tissue sections of animal models revealed perturbations in their mechanical properties, such as elevated stiffness, altered alignment of fibrillar collagens, and increased crosslinking density [6,7]. Such ECM anomalies are why tumors manifest as palpable masses during clinical diagnosis [8,9] and have been correlated to poor prognosis in patients [10,11]. As tumor cells perceive these cues, some key mechanosensing players on cellular surfaces, such as focal adhesion kinase (FAK), cadherins, and transmembrane protein complexes, like integrins and syndecans, get activated [12,13]. Consequently, these dysregulate mechanotransductive pathways by inducing aberrant transmission of forces from ECM to the nucleus. For example, aligned fibrils and enhanced crosslinking density increase integrin and caveolin-1 mediated FAK expression levels. This has been positively correlated to metastatic dissemination, matrix-independent survival, and chemotherapeutic resistance of tumor cells derived from pancreatic, head and neck squamous carcinoma (HNSCC) and breast cancer patients [14,15]. In addition, it increases the subcellular localization and activation of Yes-associated proteins (YAP) into the nucleus, which operates as an oncoprotein through which tumor cells attain enhanced migratory potential [16,17]. Abnormal ECM also directs the behavior of neighboring cells like fibroblasts, immune cells, and endothelial cells, which drive metastatic cell dissemination [18]. Quiescent fibroblasts get activated and differentiated into cancer-associated fibroblasts (CAFs), whose secretomes drive neovascularization to meet oxygen and nutrient requirements [19]. They also promote fibroplasia and the production of matrix crosslinking enzymes that amplify ECM remodeling [20]. Degrading ECM provokes the release of chemokines that increase tumor cells' capacity to veil themselves from cytotoxic T-cells (CD8+ T cells), which are the key to tumor eradication [21].

Understanding this disruption in mechanical homeostasis and how it orchestrates tumor growth is key to representing these physical properties in newly inspired in vitro biomimetic tumor platforms. Control over tissue microarchitectural features can advance the development of new and efficient ECM-targeted therapies that could be combined with chemotherapeutic drugs to potentiate efficacy. The effect of tumor microenvironment (TME) mechanics on tumor progression is often considered multifaceted; all factors interact concurrently with tumor cells and modulate their responses (Fig. 1). Here, we elucidate the various physical cues of a tumorigenic ECM and how each of them independently and significantly affect cancer cell responses. Inspired by this information, we also discuss some of the state-of-the-art strategies adopted to recapitulate these mechanical properties individually in lab grown three-dimensional (3D) culture systems for visualizing the complex interactions between cells and ECM, thereby contributing to the scientific knowledge of tumor mechanobiology.