A multiscale study revealing the interplay between tumor growth and the three-dimensional extracellular matrix

Abstract

To study biological processes of cancer progression is not an easy task – effort has been made to develop novel in vitro platforms that recapitulate physical features of the tumor microenvironment (TME) for cancer research. This dissertation covers three main topics attempting to further the effort on in vitro tumor models: (I) biomechanics of tumor growth in a three-dimensional (3D) mechanical context and local mechanical stress correlated to tumor shape; (II) the role of collagen structure in cancer progression; and (III) the intrinsic heterogeneity with which a population of cancer cells interacts with 3D matrices. Using interdisciplinary approaches, this work aims to evaluate mechanical principles and tissue architecture that regulate tumor growth and progression, and to better understand cancer heterogeneous response to 3D in vitro models. Our results may provide insights on how physical cues affect cancer cell behavior and tumor growth, and raise the awareness of the importance of cancer heterogeneity in cancer research.

In healthy tissues, biomechanical signals, such as tissue stiffness and mechanical stress, provide important governing signals that direct cell division, motility, and differentiation. Increased tissue stiffness and mechanical stress are, in general, associated with solid tumor growth; therefore, it is not surprising that biomechanical signaling becomes deregulated. Furthermore, the increased tissue stiffness is often related to overexpression and excessive crosslinking of extracellular matrix (ECM) components, such as collagen, during tumor progression. Therefore, the extracellular matrix surrounding the tumor will be reorganized and densified, which favors tumor cell invasion, the first step in metastasis. Whereas a biomechanical understanding of healthy tissue processes is being gained from governing geometric (cell shape) and biophysical (mechanical tension) cues, and their integration with the responsible molecular mechanisms is being elucidated, the same cannot be said of tumor development, which is characterized by aberrant growth patterns.