Collagen-Based Biomimetic Systems to Study the Biophysical Tumour Microenvironment

SIMPLE SUMMARY: It is increasingly acknowledged that cells in the body not only sense biochemical signals, but also feel and respond to mechanical signals. Tissues and organs, for example, have very different stiffnesses and can be very stiff like bone or soft like lungs or the gut. This difference in stiffness is mostly due to the presence of collagen, a protein present in between cells that provides structural support to organs and tissues. Together with proteins such as fibronectin, collagen forms the so-called extracellular matrix. Excessive presence or defective organization of collagen in this matrix alter the normal mechanical properties of organs and tissues and accompany diseases such as fibrosis and cancer. This review describes the systems used in the laboratory to mimic this matrix and investigate how cells respond to different mechanical forces in health and disease. ABSTRACT: The extracellular matrix (ECM) is a pericellular network of proteins and other molecules that provides mechanical support to organs and tissues. ECM biophysical properties such as topography, elasticity and porosity strongly influence cell proliferation, differentiation and migration. The cell’s perception of the biophysical microenvironment (mechanosensing) leads to altered gene expression or contractility status (mechanotransduction). Mechanosensing and mechanotransduction have profound implications in both tissue homeostasis and cancer. Many solid tumours are surrounded by a dense and aberrant ECM that disturbs normal cell functions and makes certain areas of the tumour inaccessible to therapeutic drugs. Understanding the cell-ECM interplay may therefore lead to novel and more effective therapies. Controllable and reproducible cell culturing systems mimicking the ECM enable detailed investigation of mechanosensing and mechanotransduction pathways. Here, we discuss ECM biomimetic systems. Mainly focusing on collagen, we compare and contrast structural and molecular complexity as well as biophysical properties of simple 2D substrates, 3D fibrillar collagen gels, cell-derived matrices and complex decellularized organs. Finally, we emphasize how the integration of advanced methodologies and computational methods with collagen-based biomimetics will improve the design of novel therapies aimed at targeting the biophysical and mechanical features of the tumour ECM to increase therapy efficacy.