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Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may allow us to design better protocols to prevent it, as well as provide insights into the mechanobiology of cancer development. We conducted a multiscale experimental and mathematical examination of 3D cancer growth in triple negative breast cancer cells. Migration was examined in the presence and absence of Paclitaxel, in high and low adhesion environments and in the presence of fibroblasts. The observed behaviour was modeled by hypothesizing active migration due to self-generated chemotactic gradients. Our results confirmed this hypothesis, whereby migration was likely to be regulated by the MAPK and TGF-βpathways. The mathematical model enabled us to describe the experimental data in absence (normalized error<40%) and presence of Paclitaxel (normalized error<10%), suggesting inhibition of random motion and advection in the latter case. Inhibition of sedimentation in low adhesion and co-culture experiments further supported the conclusion that cells actively migrated downwards due to the presence of signals produced by cells already attached to the adhesive glass surface. Author summary: Cell sedimentation in 3D cultures can have both advantageous and unwanted effects. On the one side, the loss of the 3rd dimension is undesirable in a 3D culture. On the other side, it can reveal interesting migration phenomena given that passive mechanisms such as gravity are not potential contributors. In this work, we examined the phenomenon of sedimentation by combining 3D cultures and spatiotemporal mathematical modelling. We found that passive mechanisms such as gravity and matrix compression are not sufficient to bring the cells at the bottom. Our analysis showed that the cells actively migrate towards the bottom and in a collective manner, suggesting the presence of chemotactic gradients produced by cells already attached to the glass surface. [ABSTRACT FROM AUTHOR]

Hyperthermia acts as a powerful adjuvant to radiation therapy and chemotherapy. Recent advances show that gold nanoparticles (Au-NPs) can mediate highly localized thermal effects upon interaction with laser radiation. The purpose of the present study was to investigate via in silico simulations the mechanisms of Au-NPs and microwave-induced hyperthermia, in correlation to predictions of tumor control (biological endpoints: tumor shrinkage and cell death) after hyperthermia treatment. We also study in detail the dependence of the size, shape and structure of the gold nanoparticles on their absorption efficiency, and provide general guidelines on how one could modify the absorption spectrum of the nanoparticles in order to meet the needs of specific applications. We calculated the hyperthermia effect using two types of Au-NPs and two types of spherical tumors (prostate and melanoma) with a radius of 3 mm. The plasmon peak for the 30 nm Si-core Au-coated NPs and the 20 nm Au-NPs was found at 590 nm and 540 nm, respectively. Considering the plasmon peaks and the distribution of NPs in the tumor tissue, the induced thermal profile was estimated for different intervals of time. Predictions of hyperthermic cell death were performed by adopting a three-state mathematical model, where "three-state" includes (i) alive, (ii) vulnerable, and (iii) dead states of the cell, and it was coupled with a tumor growth model. Our proposed methodology and preliminary results could be considered as a proof-of-principle for the significance of simulating accurately the hyperthermia-based tumor control involving the immune system. We also propose a method for the optimization of treatment by overcoming thermoresistance by biological means and specifically through the targeting of the heat shock protein 90 (HSP90), which plays a critical role in the thermotolerance of cells and tissues. [ABSTRACT FROM AUTHOR]

Mathematical models of cancer growth have become increasingly more accurate both in the space and time domains. However, the limited amount of data typically available has resulted in a larger number of qualitative rather than quantitative studies. In the present study, we provide an integrated experimental-computational framework for the quantification of the morphological characteristics and the mechanistic modelling of cancer progression in 3D environments. The proposed framework allows for the calibration of multiscale, spatiotemporal models of cancer growth using state-of-the-art 3D cell culture data, and their validation based on the resulting experimental morphological patterns using spatial point-pattern analysis techniques. We applied this framework to the study of the development of Triple Negative Breast Cancer cells cultured in Matrigel scaffolds, and validated the hypothesis of chemotactic migration using a multiscale, hybrid Keller-Segel model. The results revealed transient, non-random spatial distributions of cancer cells that consist of clustered, and dispersion patterns. The proposed model was able to describe the general characteristics of the experimental observations and suggests that chemotactic migration together with random motion was found to be a plausible mechanism leading to accumulation, during the examined time period of development. The developed framework enabled us to pursue two goals; first, the quantitative description of the morphology of cancer growth in 3D cultures using point-pattern analysis, and second, the relation of tumour morphology with underlying biophysical mechanisms that govern cancer growth and migration.