A mathematical model of tumor-endothelial interactions in a 3D co-culture

Abstract

Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essential steps during metastasis. Successful invasion requires coordinated tumor-endothelial crosstalk, utilizing mechanochemical signaling to direct cytoskeletal rearrangement for transmigration of cancer cells. However, mechanisms underlying physical interactions are difficult to observe due to the lack of experimental models easily combined with theoretical models that better elucidate these pathways. We have previously demonstrated that an engineered 3D in vitro endothelial-epithelial co-culture system can be used to isolate both molecular and physical tumor-endothelial interactions in a platform that is easily modeled, quantified, and probed for experimental investigation. Using this platform with mathematical modeling, we show that breast metastatic cells display unique behavior with the endothelium, exhibiting a 3.2-fold increase in interaction with the endothelium and a 61-fold increase in elongation compared to normal breast epithelial cells. Our mathematical model suggests energetic favorability for cellular deformation prior to breeching endothelial junctions, expending less energy as compared to undeformed cells, which is consistent with the observed phenotype. Finally, we show experimentally that pharmacological inhibition of the cytoskeleton can disrupt the elongatation and alignment of metastatic cells with endothelial tubes, reverting to a less invasive phenotype.

Inhibition of Tunneling Nanotubes between Cancer Cell and the Endothelium Alters the Metastatic Phenotype

“…We also demonstrated the phenotypic plasticity of the cancer cells during communication with endothelial cells. Metastatic human cancer cells transform their phenotype from cellular aggregates or mammosphere-like structures to an elongated phenotype when cultured with endothelial cells in 3D tumor matrix [ 9 ]. Here, we demonstrate that disrupting the nanotubes can revert this invasive phenotype to a non-invasive phenotype.…”

“…It involves a cascade of events, including break out of cancer cells from the primary tumor location, invasion and intravasation through the blood vessels, and colonization at the secondary site in the patient’s body [ 2 , 3 ]. To invade the blood vessel barrier, which is lined with endothelial cells, tumor cells communicate with the endothelial cells and impose phenotypical transition [ 4 , 5 , 6 , 7 , 8 , 9 ] to enter the circulation and achieve metastasis [ 10 , 11 , 12 ]. Cross talk between the cancer cells and the endothelial cells takes place through various cellular communications, such as paracrine signaling, through physical modalities like gap junctions, synapses, exosomes, and vesicles that contribute to cancer progress and metastasis [ 13 , 14 , 15 , 16 ].…”

Role of neutrophil extracellular traps in regulation of lung cancer invasion and metastasis: Structural insights from a computational model

“…Mathematical models of tumor microenvironment and tumor-immune system interactions have been developed: fibroblasts-tumor [ 33 – 35 ], macrophages-tumor [ 36 , 37 ], astrocytes-tumor [ 38 ], NK cells-tumor [ 39 – 41 ], neutrophil-tumor [ 42 , 43 ], tumor-endothelial [ 44 ], and immune-tumor [ 45 , 46 ] interactions. However, the detailed mechanism of tumor invasion and metastasis via communication with TANs is still poorly understood.…”

Deformation of an Encapsulated Leukemia HL60 Cell through Sudden Contractions of a Microfluidic Channel

“…These techniques are adapted and modified to model the mechanics of deformation for different types of biological cells and subcellular components such as the cytoskeleton and cell membrane [12,13]. They have utilized the deformation behavior and other mechanical properties of cancer cells to classify them [8,[14][15][16]. Healthy and unhealthy cells can be sorted based on their deformation characteristics, which is a very useful tool for cancer therapies [8].…”