Multiscale Mechanics of Cancer Metastasis to Bone

The World Health Organization reported that over one million deaths occur worldwide due to breast and prostate cancer. The majority of these deaths occur due to metastasis of the cancer to distant locations in the body, which for breast cancer and prostate cancer happens to be bone. At the bone site, the cancer cells colonize, proliferate, and have a very detrimental impact on the bone. Clinically, this is manifested as frequent skeletal failures. In order to recapitulate the metastasis process through a realistic testbed, we have developed an in vitro model of bone metastasis using nanoclay bone mimetic scaffolds. Experiments using commercial and patient-derived cancer cell lines to create metastasized tumors indicate significant changes to the morphology of the cancer cells based on the cancer phenotype. Also, depending on the phenotype, the mechanical properties of the cancer cells extracted from the tumors are dramatically altered. Associated with the observed changes, we observe significant changes in gene expressions related to actin and actin depolymerization factor cofilin (ADF/cofilin). Confocal imaging of cancer tumors during cancer progression reveals significant actin dynamics, both quantitatively and spatially. Label-free discrimination of cancer progression using Raman imaging and cluster analysis also reveals actin dynamics and changes to actin-related bands, which could serve as spectral biomarkers for cancer progression at the bone site. Steered molecular dynamics simulations of actin and actin with ADF/cofilin describe the mechanisms of the resilience of actin molecules and depolymerization of actin by ADF/cofilin, critical players in the actin dynamics during the cancer progression. Hence, actin remodeling plays a vital role in cancer metastasis progression and pertains to cellular behavior inside the cell. In order to evaluate the molecular phenomena outside the cell, we investigate the characteristics of integrin molecules. The integrin protein is a mechanotransducer establishing mechanical reciprocity between the extracellular matrix and cells at integrin-based adhesion sites. This protein plays a critical role in cell-ECM adhesion and cellular signaling. We conducted steered molecular dynamics (SMD) simulations to investigate the mechanical responses of integrin αvβ3 with and without ligand binding for a variety of mechanical loading paths. The ligand-binding integrin confirmed the integrin activation during equilibration by opening the hinge between βA and the hybrid domain. This activation of liganded αvβ3 integrin influenced the molecule's stiffness observed during tensile loading. Furthermore, we observed that the interface interaction between β-tail, hybrid, and epidermal growth factor domains altered integrin dynamics. The deformation of extended integrin models in the bending and unbending directions of integrin reveals the stored folding energy and the directionally dependent stiffnesses of the integrin molecule. Along with experimental data, the SMD simulations were used to evaluate the mechanical properties of integrin and identify the underlying mechanisms of integrin-based adhesion substrates. The investigation of the mechanics of integrin molecules provides new insights into understanding the mechanotransmission between cells, ECM, and the substrate. Overall the mechanotransduction facilitated by integrins to actin remodeling at the cellular insides is a critical molecular phenomenon that exists over a multiscale regime that synergistically creates the metastasis progression of cancer.