Tumor associated angiogenesis is the development of new blood vessels in response to proteins secreted by tumor cells. These new blood vessels allow tumors to continue to grow beyond what the pre-existing vasculature could support. Here, we construct a mathematical model to simulate tumor angiogenesis by considering each endothelial cell as an agent, and allowing the vascular endothelial growth factor (VEGF) and nutrient fields to impact the dynamics and phenotypic transitions of each tumor and endothelial cell. The phenotypes of the endothelial cells (i.e., tip, stalk, and phalanx cells) are selected by the local VEGF field, and govern the migration and growth of vessel sprouts at the cellular level. Over time, these vessels grow and migrate to the tumor, forming anastomotic loops to supply nutrients, while interacting with the tumor through mechanical forces and the consumption of VEGF. The model is able to capture collapsing and breaking of vessels caused by tumor-endothelial cell interactions. This is accomplished through modeling the physical interaction between the vasculature and the tumor, resulting in vessel occlusion and tumor heterogeneity over time due to the stages of response in angiogenesis. Key parameters are identified through a sensitivity analysis based on the Sobol method, establishing which parameters should be the focus of subsequent experimental efforts. During the avascular phase (i.e., before angiogenesis is triggered), the nutrient consumption rate, followed by the rate of nutrient diffusion, yield the greatest influence on the number and distribution of tumor cells. Similarly, the consumption and diffusion of VEGF yield the greatest influence on the endothelial and tumor cell numbers during angiogenesis. In summary, we present a hybrid mathematical approach that characterizes vascular changes via an agent-based model, while treating nutrient and VEGF changes through a continuum model. The model describes the physical interaction between a tumor and the surrounding blood vessels, explicitly allowing the forces of the growing tumor to influence the nutrient delivery of the vasculature.
Tumor-associated vasculature is responsible for the delivery of nutrients, removal of waste, and allowing growth beyond 2–3 mm3. Additionally, the vascular network, which is changing in both space and time, fundamentally influences tumor response to both systemic and radiation therapy. Thus, a robust understanding of vascular dynamics is necessary to accurately predict tumor growth, as well as establish optimal treatment protocols to achieve optimal tumor control. Such a goal requires the intimate integration of both theory and experiment. Quantitative and time-resolved imaging methods have emerged as technologies able to visualize and characterize tumor vascular properties before and during therapy at the tissue and cell scale. Parallel to, but separate from those developments, mathematical modeling techniques have been developed to enable in silico investigations into theoretical tumor and vascular dynamics. In particular, recent efforts have sought to integrate both theory and experiment to enable data-driven mathematical modeling. Such mathematical models are calibrated by data obtained from individual tumor-vascular systems to predict future vascular growth, delivery of systemic agents, and response to radiotherapy. In this review, we discuss experimental techniques for visualizing and quantifying vascular dynamics including magnetic resonance imaging, microfluidic devices, and confocal microscopy. We then focus on the integration of these experimental measures with biologically based mathematical models to generate testable predictions.
Inflammatory breast cancer (IBC), a rare form of breast cancer associated with increased angiogenesis and metastasis, is largely driven by tumor-stromal interactions with the vasculature and the extracellular matrix (ECM). However, there is currently a lack of understanding of the role these interactions play in initiation and progression of the disease. In this study, we developed the first three-dimensional, in vitro, vascularized, microfluidic IBC platform to quantify the spatial and temporal dynamics of tumor-vasculature and tumor-ECM interactions specific to IBC. Platforms consisting of collagen type 1 ECM with an endothelialized blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149 (triple negative), and for comparison to non-IBC cells, MDA-MB-231 (triple negative). Acellular collagen platforms with endothelialized blood vessels served as controls. SUM149 and MDA-MB-231 platforms exhibited a significantly (p < .05) higher vessel permeability and decreased endothelial coverage of the vessel lumen compared to the control.
Summary We provide an overview on the use of biological assays to calibrate and initialize mechanism-based models of cancer phenomena. Although artificial intelligence methods currently dominate the landscape in computational oncology, mathematical models that seek to explicitly incorporate biological mechanisms into their formalism are of increasing interest. These models can guide experimental design and provide insights into the underlying mechanisms of cancer progression. Historically, these models have included a myriad of parameters that have been difficult to quantify in biologically relevant systems, limiting their practical insights. Recently, however, there has been much interest calibrating biologically based models with the quantitative measurements available from (for example) RNA sequencing, time-resolved microscopy, and in vivo imaging. In this contribution, we summarize how a variety of experimental methods quantify tumor characteristics from the molecular to tissue scales and describe how such data can be directly integrated with mechanism-based models to improve predictions of tumor growth and treatment response.
Hybrid multiscale agent-based models (ABMs) are unique in their ability to simulate individual cell interactions and microenvironmental dynamics. Unfortunately, the high computational cost of modeling individual cells, the inherent stochasticity of cell dynamics, and numerous model parameters are fundamental limitations of applying such models to predict tumor dynamics. To overcome these challenges, we have developed a coarse-grained two-scale ABM (cgABM) with a reduced parameter space that allows for an accurate and efficient calibration using a set of time-resolved microscopy measurements of cancer cells grown with different initial conditions. The multiscale model consists of a reaction-diffusion type model capturing the spatio-temporal evolution of glucose and growth factors in the tumor microenvironment (at tissue scale), coupled with a lattice-free ABM to simulate individual cell dynamics (at cellular scale). The experimental data consists of BT474 human breast carcinoma cells initialized with different glucose concentrations and tumor cell confluences. The confluence of live and dead cells was measured every three hours over four days. Given this model, we perform a time-dependent global sensitivity analysis to identify the relative importance of the model parameters. The subsequent cgABM is calibrated within a Bayesian framework to the experimental data to estimate model parameters, which are then used to predict the temporal evolution of the living and dead cell populations. To this end, a moment-based Bayesian inference is proposed to account for the stochasticity of the cgABM while quantifying uncertainties due to limited temporal observational data. The cgABM reduces the computational time of ABM simulations by 93% to 97% while staying within a 3% difference in prediction compared to ABM. Additionally, the cgABM can reliably predict the temporal evolution of breast cancer cells observed by the microscopy data with an average error and standard deviation for live and dead cells being 7.61±2.01 and 5.78±1.13, respectively.
Digital twins employ mathematical and computational models to virtually represent a physical object (e.g., planes and human organs), predict the behavior of the object, and enable decision-making to optimize the future behavior of the object. While digital twins have been widely used in engineering for decades, their applications to oncology are only just emerging. Due to advances in experimental techniques quantitatively characterizing cancer, as well as advances in the mathematical and computational sciences, the notion of building and applying digital twins to understand tumor dynamics and personalize the care of cancer patients has been increasingly appreciated. In this review, we present the opportunities and challenges of applying digital twins in clinical oncology, with a particular focus on integrating medical imaging with mechanism-based, tissue-scale mathematical modeling. Specifically, we first introduce the general digital twin framework and then illustrate existing applications of image-guided digital twins in healthcare. Next, we detail both the imaging and modeling techniques that provide practical opportunities to build patient-specific digital twins for oncology. We then describe the current challenges and limitations in developing image-guided, mechanism-based digital twins for oncology along with potential solutions. We conclude by outlining five fundamental questions that can serve as a roadmap when designing and building a practical digital twin for oncology and attempt to provide answers for a specific application to brain cancer. We hope that this contribution provides motivation for the imaging science, oncology, and computational communities to develop practical digital twin technologies to improve the care of patients battling cancer.
Hybrid multiscale agent-based models (ABMs) are unique in their ability to simulate individual cell interactions and microenvironmental dynamics. Unfortunately, the high computational cost of modeling individual cells, the inherent stochasticity due to probabilistic phenotypic transitions, and numerous model parameters that are difficult to measure directly are fundamental limitations of applying such models to predict tumor dynamics. To overcome these challenges, we have developed a coarse-grained two-scale ABM (cgABM) calibrated with a set of time-resolved microscopy measurements of cancer cells grown with different initial conditions. The multiscale model consists of a reaction-diffusion type model capturing the spatio-temporal evolution of glucose and growth factors in the tumor microenvironment (at tissue scale), coupled with a lattice-free ABM to simulate individual cell dynamics (at cellular scale). The experimental data consists of BT474 human breast carcinoma cells initialized with different glucose concentrations and tumor cell confluences. The confluence of live and dead cells was measured every three hours over four days. Given this model and data, we perform a global sensitivity analysis to identify the relative importance of the model parameters. The subsequent cgABM with a reduced parameter space is calibrated within a Bayesian framework to the experimental data to estimate model parameters, which are then used to predict the temporal evolution of the living and dead cell populations. To this end, a moment-based Bayesian inference is proposed to account for the stochasticity of the cgABM while quantifying uncertainties in model parameters and observational data. The results indicate that the cgABM can reliably predict the spatiotemporal evolution of breast cancer cells observed by the microscopy data with an average error and standard deviation for live and dead cells being 7.61 [[EQUATION]] 2.01 and 5.78 [[EQUATION]] 1.13, respectively.
A Ni-catalyzed annulation reaction to synthesize indenones is reported. The reaction provides high yields and regioselectivities when aliphatic- and silyl-substituted alkynes are employed. Both have been challenging and underutilized substrate classes. Several mechanistic observations aided in the development of this reaction, including that β-hydride elimination is turnover-limiting for ortho-halogenated aldehyde substrates and that alkyne dissociation is rate-limiting for internal aliphatic alkynes. We anticipate that these methods will be rapidly adopted due to their synthetic ease and inherent versatility. We also anticipate that the mechanistic conclusions will inform further reaction development.
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