More Like this

1. Growth of tumor emboli within a vessel model reveals dependence on the magnitude of mechanical constraint

   https://doi.org/10.1093/intbio/zyaa024  

   Kulwatno, Jonathan; Gearhart, Jamie; Gong, Xiangyu; Herzog, Nora; Getzin, Matthew; Skobe, Mihaela; Mills, Kristen L (January 2021, Integrative Biology)

   null (Ed.)

   ABSTRACT Tumor emboli—aggregates of tumor cells within vessels—pose a clinical challenge as they are associated with increased metastasis and tumor recurrence. When growing within a vessel, tumor emboli are subject to a unique mechanical constraint provided by the tubular geometry of the vessel. Current models of tumor emboli use unconstrained multicellular tumor spheroids, which neglect this mechanical interplay. Here, we modeled a lymphatic vessel as a 200 μm-diameter channel in either a stiff or soft, bioinert agarose matrix to create a vessel-like constraint model (VLCM), and we modeled colon or breast cancer tumor emboli with aggregates of HCT116 or SUM149PT cells, respectively. The stiff matrix VLCM constrained the tumor emboli to the cylindrical channel, which led to continuous growth of the emboli, in contrast to the growth rate reduction that unconstrained spheroids exhibit. Emboli morphology in the soft matrix VLCM, however, was dependent on the magnitude of mechanical mismatch between the matrix and the cell aggregates. In general, when the elastic modulus of the matrix of the VLCM was greater than the emboli (EVLCM/Eemb > 1), the emboli were constrained to grow within the channel, and when the elastic modulus of the matrix was less than the emboli (0 < EVLCM/Eemb < 1), the emboli bulged into the matrix. Due to a large difference in myosin II expression between the cell lines, we hypothesized that tumor cell aggregate stiffness is an indicator of cellular force-generating capability. Inhibitors of myosin-related force generation decreased the elastic modulus and/or increased the stress relaxation of the tumor cell aggregates, effectively increasing the mechanical mismatch. The increased mechanical mismatch after drug treatment was correlated with increased confinement of tumor emboli growth along the channel, which may translate to increased tumor burden due to the increased tumor volume within the diffusion distance of nutrients and oxygen. 

   more » « less
2. Collagen density regulates tip–stalk cell rearrangement during angiogenesis via cellular bioenergetics

   https://doi.org/10.1063/5.0195249  

   Wang, Wenjun; Zanotelli, Matthew_R; Sabo, Lindsey_N; Fabiano, Emily_D; Goldfield, Natalie_M; Le, Chloe; Techasiriwan, Elle_P; Lopez, Santiago; Berestesky, Emily_D; Reinhart-King, Cynthia_A (June 2024, APL Bioengineering)

   Tumor vasculature plays a crucial role in tumor progression, affecting nutrition and oxygen transportation as well as the efficiency of drug delivery. While targeting pro-angiogenic growth factors has been a significant focus for treating tumor angiogenesis, recent studies indicate that metabolism also plays a role in regulating endothelial cell behavior. Like cancer cells, tumor endothelial cells undergo metabolic changes that regulate rearrangement for tip cell position during angiogenesis. Our previous studies have shown that altered mechanical properties of the collagen matrix regulate angiogenesis and can promote a tumor vasculature phenotype. Here, we examine the effect of collagen density on endothelial cell tip–stalk cell rearrangement and cellular energetics during angiogenic sprouting. We find that increased collagen density leads to an elevated energy state and an increased rate of tip–stalk cell switching, which is correlated with the energy state of the cells. Tip cells exhibit higher glucose uptake than stalk cells, and inhibition of glucose uptake revealed that invading sprouts rely on glucose to meet elevated energy requirements for invasion in dense matrices. This work helps to elucidate the complex interplay between the mechanical microenvironment and the endothelial cell metabolic status during angiogenesis, which could have important implications for developing new anti-cancer therapies. 

   more » « less
3. Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach

   https://doi.org/10.1038/s41598-020-78780-7  

   Wang, Yafei; Brodin, Erik; Nishii, Kenichiro; Frieboes, Hermann B.; Mumenthaler, Shannon M.; Sparks, Jessica L.; Macklin, Paul (January 2021, Scientific Reports)

   Abstract Colorectal cancer and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could “reawaken” after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer. 

   more » « less
4. Introduction of Heterogeneous Cell Properties for Modeling Emergent Stress Fields in Multicellular Systems

   Goldblatt, Zachary E; Cirka, Heather A; Ashouri Choshali, Habibeh; Rahbar, Nima; McCollum, Dannel; Billiar, Kristen L (June 2019, Summer Biomechanics, Biotransport, and Bioengineering Meeting)

   We present the first experimental evidence that supports that low stresses are experienced by central cells and is driving the biological response of aggregates. Our model improves upon previous models, however, it can still become more robust. We plan to obtain higher resolution biophysical data with validation to further alter cell contractility distributions and iterate our model’s parameters. It is necessary to incorporate heterogeneous mechanical properties to accurately estimate the distribution of the emergent stress fields in our aggregates. 

   more » « less
5. Incorporating tissue anisotropy and heterogeneity in finite element models of trabecular bone altered predicted local stress distributions

   https://doi.org/10.1007/s10237-017-0981-8  

   Hammond, Max A.; Wallace, Joseph M.; Allen, Matthew R.; Siegmund, Thomas (November 2017, Biomechanics and Modeling in Mechanobiology)

   Trabecular bone is composed of organized mineralized collagen fibrils, which results in heterogeneous and anisotropic mechanical properties at the tissue level. Recently, biomechanical models computing stresses and strains in trabecular bone have indicated a significant effect of tissue heterogeneity on predicted stresses and strains. How-ever, the effect of the tissue-level mechanical anisotropy on the trabecular bone biomechanical response is unknown. Here, a computational method was established to automatically impose physiologically relevant orientation inherent in trabecular bone tissue on a trabecular bone microscale finite element model. Spatially varying tissue-level anisotropic elastic properties were then applied according to the bone mineral density and the local tissue orientation. The model was used to test the hypothesis that anisotropy in both homogeneous and heterogeneous models alters the predicted distribution of stress invariants. Linear elastic finite element computations were performed on a 3 mm cube model isolated from a microcomputed tomography scan of human trabecular bone from the distal femur. Hydrostatic stress and von Mises equivalent stress were recorded at every element, and the distributions of these values were analyzed. Anisotropy reduced the range of hydrostatic stress in both tension and compression more strongly than the associated increase in von Mises equivalent stress. The effect of anisotropy was independent of the spatial redistribution high compressive stresses due to tissue elastic heterogeneity. Tissue anisotropy and heterogeneity are likely important mechanisms to protect bone from failure and should be included for stress analyses in trabecular bone. 

   more » « less