Abstract
Changes in extracellular matrix (ECM) structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1)-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics) to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.
Highlights
Cancer is commonly thought of as a genetic disease, resulting from a series of gene mutations that deregulate cell growth and lead to neoplastic transformation
Computational Model of Tissue Homeostasis The cells and tissues of every organ exhibit characteristic threedimensional (3D) shapes that are highly regular in form, whereas cell and tissue shape become progressively disorganized during tumor formation and cancer progression
We described a simulation model in which increased variability in phenotypic cell parameters, caused by structural variations in tissue microenvironments that alter the number of cell neighbors and cell shape, can lead to sustained growth pathologies that are consistent with cancer progression
Summary
Cancer is commonly thought of as a genetic disease, resulting from a series of gene mutations that deregulate cell growth and lead to neoplastic transformation. While gene mutations contribute to carcinogenesis, recent work has revealed that changes in the tissue microenvironment can initiate and drive cancer formation. Breast cancer progression is accompanied by progressive increases in ECM stiffness, and breast cancer growth can be selectively accelerated or slowed by respectively increasing or decreasing ECM cross-linking in vivo [9,10]. Breast cancer cells have been shown to undergo a phenotypic reversion in vitro when physically compressed [11]. While the importance of the physical nature of the tumor microenvironment is well appreciated, the mechanism by which these changes might drive (or reverse) cancer formation remains unclear
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