Abstract
Biomechanical alterations to the tumor microenvironment include accumulation of solid stresses, extracellular matrix (ECM) stiffening and increased fluid pressure in both interstitial and peri-tumoral spaces. The relationship between interstitial fluid pressurization and ECM remodeling in vascularized tumors is well characterized, while earlier biomechanical changes occurring during avascular tumor growth within the peri-tumoral ECM remain poorly understood. Type I collagen, the primary fibrous ECM constituent, bears load in tension while it buckles under compression. We hypothesized that tumor-generated compressive forces cause collagen remodeling via densification which in turn creates a barrier to convective fluid transport and may play a role in tumor progression and malignancy. To better understand this process, we characterized the structure-function relationship of collagen networks under compression both experimentally and computationally. Here we show that growth of epithelial cancers induces compressive remodeling of the ECM, documented in the literature as a TACS-2 phenotype, which represents a localized densification and tangential alignment of peri-tumoral collagen. Such compressive remodeling is caused by the unique features of collagen network mechanics, such as fiber buckling and cross-link rupture, and reduces the overall hydraulic permeability of the matrix.
Highlights
Genomic instability is the primary driver of tumor initiation, disease progression is increasingly recognized to be promoted by pathologic interactions between a tumor and its microenvironment, including exchange of mechanical forces with a remodeled extracellular matrix (ECM)[1,2]
Www.nature.com/scientificreports presence of tensional forces generated by contractile metastatic cells[13], it can be reasoned that the presence of tumor-associated collagen signatures (TACS)-2 is instead associated with an earlier stage of disease in which compressive forces are applied to the ECM by uncontrolled proliferation, little quantitative evidence has been provided so far
Our results suggest that tumor growth induces compressive remodeling, a localized densification of collagen caused by fiber bending and cross-link rupture, which in turn reduces the hydraulic permeability of the peri-tumoral matrix
Summary
Genomic instability is the primary driver of tumor initiation, disease progression is increasingly recognized to be promoted by pathologic interactions between a tumor and its microenvironment, including exchange of mechanical forces with a remodeled extracellular matrix (ECM)[1,2]. Albeit computational models have established a link between tumor growth, mechanical compression of collagen, and increased peri-tumoral interstitial fluid pressure via a reduced hydraulic permeability of the matrix[19,20], the mechanisms underlying the structural and functional consequences of such compressive remodeling in collagen networks remain unknown. To fill this gap, here we used spheroids of epithelial breast cancer cells embedded in fibrous collagen to provide quantitative evidence of mechanical compression upon spheroid growth, and investigated the mechanical basis of compressive remodeling of collagen by combining biomechanical experiments with biophysical modeling of collagen network mechanics. Our results suggest that tumor growth induces compressive remodeling, a localized densification of collagen caused by fiber bending and cross-link rupture, which in turn reduces the hydraulic permeability of the peri-tumoral matrix
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