Extracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells Claudia Tanja Mierke Abstract: Extracellular biophysical properties significantly influence a wide range of cellular behaviors and functions, including growth, motility, differentiation, apoptosis, gene expression, cell–matrix and cell–cell adhesion, and signal transduction, including mechanotransduction. Cells not only respond to mechanical cues from the extracellular matrix (ECM), but can also manipulate the mechanical features of the matrix in parallel with biological characteristics, interfering with downstream matrix-based cues in both physiological and pathological processes. Bidirectional interactions between cells and (bio)materials in vitro can alter cell phenotype and mechanotransduction, as well as ECM structure, intentionally or unintentionally. Interactions between cell and matrix mechanics in vivo are particularly important in various diseases, including primarily cancer. Stiffness values between normal and cancerous tissue can range from 500 Pa (soft) to 48 kPa (stiff). Even shear flow can increase from 0.1–1 dyn/cm² (normal tissue) to 1–10 dyn/cm² (cancerous tissue). There are currently many new areas of activity in tumor research on various biological length scales, which are highlighted in this review. Moreover, the complexity of interactions between ECM and cancer cells is reduced to common features of different tumors and the characteristics are highlighted to identify the main pathways of interaction. This all contributes to the standardization of mechanotransduction models and approaches, which, ultimately, increases the understanding of the complex interaction. Finally, both the in vitro and in vivo effects of this mechanics–biology pairing have key insights and implications for clinical practice in tumor treatment and, consequently, clinical translation. Keywords: extracellular matrix (ECM) remodeling; fibronectin; cell mechanics; cancer cells; EMT; immune cells; plasticity; mechanosensing; cancer-associated fibroblasts (CAFs) The extracellular matrix (ECM) is a complex, dynamic, and crosslinked reticulation that contains tethered biomolecules. The proper function of tissues and entire organs relies on the function of the ECM scaffold. It provides vital physical sustenance to cells and produces key biochemical and biomechanical cues necessary for the development of tissues. The ECM is generated and remodeled by dynamic, reciprocal, biochemical, and biophysical interactions between the ECM and various cells, such as fibroblasts, cancer-associated fibroblasts (CAFs), adipocytes, cancer-associated adipocytes, cancer-associated macrophages, cancer cells, and stem cells. These interactions play a role in numerous physiological and pathological processes, involving homeostasis, aging, wound healing, and multiple diseases, like cancer, fibrosis, and cardiovascular and pulmonary pathologies. Altering the interactions between the ECM and cells may help to regulate cell behavior, offering great potentialExtracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells Claudia Tanja Mierke Abstract: Extracellular biophysical properties significantly influence a wide range of cellular behaviors and functions, including growth, motility, differentiation, apoptosis, gene expression, cell–matrix and cell–cell adhesion, and signal transduction, including mechanotransduction. Cells not only respond to mechanical cues from the extracellular matrix (ECM), but can also manipulate the mechanical features of the matrix in parallel with biological characteristics, interfering with downstream matrix-based cues in both physiological and pathological processes. Bidirectional interactions between cells and (bio)materials in vitro can alter cell phenotype and mechanotransduction, as well as ECM structure, intentionally or unintentionally. Interactions between cell and matrix mechanics in vivo are particularly important in various diseases, including primarily cancer. Stiffness values between normal and cancerous tissue can range from 500 Pa (soft) to 48 kPa (stiff). Even shear flow can increase from 0.1–1 dyn/cm² (normal tissue) to 1–10 dyn/cm² (cancerous tissue). There are currently many new areas of activity in tumor research on various biological length scales, which are highlighted in this review. Moreover, the complexity of interactions between ECM and cancer cells is reduced to common features of different tumors and the characteristics are highlighted to identify the main pathways of interaction. This all contributes to the standardization of mechanotransduction models and approaches, which, ultimately, increases the understanding of the complex interaction. Finally, both the in vitro and in vivo effects of this mechanics–biology pairing have key insights and implications for clinical practice in tumor treatment and, consequently, clinical translation. Keywords: extracellular matrix (ECM) remodeling; fibronectin; cell mechanics; cancer cells; EMT; immune cells; plasticity; mechanosensing; cancer-associated fibroblasts (CAFs) The extracellular matrix (ECM) is a complex, dynamic, and crosslinked reticulation that contains tethered biomolecules. The proper function of tissues and entire organs relies on the function of the ECM scaffold. It provides vital physical sustenance to cells and produces key biochemical and biomechanical cues necessary for the development of tissues. The ECM is generated and remodeled by dynamic, reciprocal, biochemical, and biophysical interactions between the ECM and various cells, such as fibroblasts, cancer-associated fibroblasts (CAFs), adipocytes, cancer-associated adipocytes, cancer-associated macrophages, cancer cells, and stem cells. These interactions play a role in numerous physiological and pathological processes, involving homeostasis, aging, wound healing, and multiple diseases, like cancer, fibrosis, and cardiovascular and pulmonary pathologies. Altering the interactions between the ECM and cells may help to regulate cell behavior, offering great potential