Connecting Agent-Based Models with High-Dimensional Parameter Spaces to Multidimensional Data Using SMoRe ParS: A Surrogate Modeling Approach.

Across a broad range of disciplines, agent-based models (ABMs) are increasingly utilized for replicating, predicting, and understanding complex systems and their emergent behavior. In the biological and biomedical sciences, researchers employ ABMs to elucidate complex cellular and molecular interactions across multiple scales under varying conditions. Data generated at these multiple scales, however, presents a computational challenge for robust analysis with ABMs. Indeed, calibrating ABMs remains an open topic of research due to their own high-dimensional parameter spaces. In response to these challenges, we extend and validate our novel methodology, Surrogate Modeling for Reconstructing Parameter Surfaces (SMoRe ParS), arriving at a computationally efficient framework for connecting high dimensional ABM parameter spaces with multidimensional data. Specifically, we modify SMoRe ParS to initially confine high dimensional ABM parameter spaces using unidimensional data, namely, single time-course information of in vitro cancer cell growth assays. Subsequently, we broaden the scope of our approach to encompass more complex ABMs and constrain parameter spaces using multidimensional data. We explore this extension with in vitro cancer cell inhibition assays involving the chemotherapeutic agent oxaliplatin. For each scenario, we validate and evaluate the effectiveness of our approach by comparing how well ABM simulations match the experimental data when using SMoRe ParS-inferred parameters versus parameters inferred by a commonly used direct method. In so doing, we show that our approach of using an explicitly formulated surrogate model as an interlocutor between the ABM and the experimental data effectively calibrates the ABM parameter space to multidimensional data. Our method thus provides a robust and scalable strategy for leveraging multidimensional data to inform multiscale ABMs and explore the uncertainty in their parameters.

Investigating Two Modes of Cancer-Associated Antigen Heterogeneity in an Agent-Based Model of Chimeric Antigen Receptor T-Cell Therapy.

Chimeric antigen receptor (CAR) T-cell therapy has been successful in treating liquid tumors but has had limited success in solid tumors. This work examines unanswered questions regarding CAR T-cell therapy using computational modeling, such as, what percentage of the tumor must express cancer-associated antigens for treatment to be successful? The model includes cancer cell and vascular and CAR T-cell modules that interact with each other. We compare two different models of antigen expression on tumor cells, binary (in which cancer cells are either susceptible or are immune to CAR T-cell therapy) and gradated (where each cancer cell has a probability of being killed by a CAR T-cell). We vary the antigen expression levels within the tumor and determine how effective each treatment is for the two models. The simulations show that the gradated antigen model eliminates the tumor under more parameter values than the binary model. Under both models, shielding, in which the low/non-antigen-expressing cells protect high antigen-expressing cells, reduced the efficacy of CAR T-cell therapy. One prediction is that a combination of CAR T-cell therapies that targets the general population of cells as well as one that specifically targets cancer stem cells should increase its efficacy.

SMoRe ParS: A novel methodology for bridging modeling modalities and experimental data applied to 3D vascular tumor growth.

Multiscale systems biology is having an increasingly powerful impact on our understanding of the interconnected molecular, cellular, and microenvironmental drivers of tumor growth and the effects of novel drugs and drug combinations for cancer therapy. Agent-based models (ABMs) that treat cells as autonomous decision-makers, each with their own intrinsic characteristics, are a natural platform for capturing intratumoral heterogeneity. Agent-based models are also useful for integrating the multiple time and spatial scales associated with vascular tumor growth and response to treatment. Despite all their benefits, the computational costs of solving agent-based models escalate and become prohibitive when simulating millions of cells, making parameter exploration and model parameterization from experimental data very challenging. Moreover, such data are typically limited, coarse-grained and may lack any spatial resolution, compounding these challenges. We address these issues by developing a first-of-its-kind method that leverages explicitly formulated surrogate models (SMs) to bridge the current computational divide between agent-based models and experimental data. In our approach, Surrogate Modeling for Reconstructing Parameter Surfaces (SMoRe ParS), we quantify the uncertainty in the relationship between agent-based model inputs and surrogate model parameters, and between surrogate model parameters and experimental data. In this way, surrogate model parameters serve as intermediaries between agent-based model input and data, making it possible to use them for calibration and uncertainty quantification of agent-based model parameters that map directly onto an experimental data set. We illustrate the functionality and novelty of Surrogate Modeling for Reconstructing Parameter Surfaces by applying it to an agent-based model of 3D vascular tumor growth, and experimental data in the form of tumor volume time-courses. Our method is broadly applicable to situations where preserving underlying mechanistic information is of interest, and where computational complexity and sparse, noisy calibration data hinder model parameterization.

Dynamic Changes in Microvascular Flow Conductivity and Perfusion After Myocardial Infarction Shown by Image-Based Modeling.

Background Microcirculation is a decisive factor in tissue reperfusion inadequacy following myocardial infarction ( MI ). Nonetheless, experimental assessment of blood flow in microcirculation remains a bottleneck. We sought to model blood flow properties in coronary microcirculation at different time points after MI and to compare them with healthy conditions to obtain insights into alterations in cardiac tissue perfusion. Methods and Results We developed an image-based modeling framework that permitted feeding a continuum flow model with anatomical data previously obtained from the pig coronary microvasculature to calculate physiologically meaningful permeability tensors. The tensors encompassed the microvascular conductivity and were also used to estimate the arteriole-venule drop in pressure and myocardial blood flow. Our results indicate that the tensors increased in a bimodal pattern at infarcted areas on days 1 and 7 after MI while a nonphysiological decrease in arteriole-venule drop in pressure was observed; contrary, the tensors and the arteriole-venule drop in pressure on day 3 after MI , and in remote areas, were closer to values for healthy tissue. Myocardial blood flow calculated using the condition-dependent arteriole-venule drop in pressure decreased in infarcted areas. Last, we simulated specific modes of vascular remodeling, such as vasodilation, vasoconstriction, or pruning, and quantified their distinct impact on microvascular conductivity. Conclusions Our study unravels time- and region-dependent alterations of tissue perfusion related to the structural changes occurring in the coronary microvasculature due to MI . It also paves the way for conducting simulations in new therapeutic interventions in MI and for image-based microvascular modeling by applying continuum flow models in other biomedical scenarios.

Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment.

Multiscale systems biology and systems pharmacology are powerful methodologies that are playing increasingly important roles in understanding the fundamental mechanisms of biological phenomena and in clinical applications. In this review, we summarize the state of the art in the applications of agent-based models (ABM) and hybrid modeling to the tumor immune microenvironment and cancer immune response, including immunotherapy. Heterogeneity is a hallmark of cancer; tumor heterogeneity at the molecular, cellular, and tissue scales is a major determinant of metastasis, drug resistance, and low response rate to molecular targeted therapies and immunotherapies. Agent-based modeling is an effective methodology to obtain and understand quantitative characteristics of these processes and to propose clinical solutions aimed at overcoming the current obstacles in cancer treatment. We review models focusing on intra-tumor heterogeneity, particularly on interactions between cancer cells and stromal cells, including immune cells, the role of tumor-associated vasculature in the immune response, immune-related tumor mechanobiology, and cancer immunotherapy. We discuss the role of digital pathology in parameterizing and validating spatial computational models and potential applications to therapeutics.

Author Correction: Deciphering microvascular changes after myocardial infarction through 3D fully automated image analysis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Modeling triple-negative breast cancer heterogeneity: Effects of stromal macrophages, fibroblasts and tumor vasculature.

A hallmark of breast tumors is its spatial heterogeneity that includes its distribution of cancer stem cells and progenitor cells, but also heterogeneity in the tumor microenvironment. In this study we focus on the contributions of stromal cells, specifically macrophages, fibroblasts, and endothelial cells on tumor progression. We develop a computational model of triple-negative breast cancer based on our previous work and expand it to include macrophage infiltration, fibroblasts, and angiogenesis. In vitro studies have shown that the secretomes of tumor-educated macrophages and fibroblasts increase both the migration and proliferation rates of triple-negative breast cancer cells. In vivo studies also demonstrated that blocking signaling of selected secreted factors inhibits tumor growth and metastasis in mouse xenograft models. We investigate the influences of increased migration and proliferation rates on tumor growth, the effect of the presence on fibroblasts or macrophages on growth and morphology, and the contributions of macrophage infiltration on tumor growth. We find that while the presence of macrophages increases overall tumor growth, the increase in macrophage infiltration does not substantially increase tumor growth and can even stifle tumor growth at excessive rates.

Deciphering microvascular changes after myocardial infarction through 3D fully automated image analysis.

The microvasculature continuously adapts in response to pathophysiological conditions to meet tissue demands. Quantitative assessment of the dynamic changes in the coronary microvasculature is therefore crucial in enhancing our knowledge regarding the impact of cardiovascular diseases in tissue perfusion and in developing efficient angiotherapies. Using confocal microscopy and thick tissue sections, we developed a 3D fully automated pipeline that allows to precisely reconstruct the microvasculature and to extract parameters that quantify all its major features, its relation to smooth muscle actin positive cells and capillary diffusion regions. The novel pipeline was applied in the analysis of the coronary microvasculature from healthy tissue and tissue at various stages after myocardial infarction (MI) in the pig model, whose coronary vasculature closely resembles that of human tissue. We unravelled alterations in the microvasculature, particularly structural changes and angioadaptation in the aftermath of MI. In addition, we evaluated the extracted knowledge's potential for the prediction of pathophysiological conditions in tissue, using different classification schemes. The high accuracy achieved in this respect, demonstrates the ability of our approach not only to quantify and identify pathology-related changes of microvascular beds, but also to predict complex and dynamic microvascular patterns.

An agent-based model of triple-negative breast cancer: the interplay between chemokine receptor CCR5 expression, cancer stem cells, and hypoxia.

BACKGROUND: Triple-negative breast cancer lacks estrogen, progesterone, and HER2 receptors and is thus not possible to treat with targeted therapies for these receptors. Therefore, a greater understanding of triple-negative breast cancer is necessary for the treatment of this cancer type. In previous work from our laboratory, we found that chemokine ligand-receptor CCL5-CCR5 axis is important for the metastasis of human triple-negative breast cancer cell MDA-MB-231 to the lymph nodes and lungs, in a mouse xenograft model. We collected relevant experimental data from our and other laboratories for numbers of cancer stem cells, numbers of CCR5+ cells, and cell migration rates for different breast cancer cell lines and different experimental conditions. RESULTS: Using these experimental data we developed an in silico agent-based model of triple-negative breast cancer that considers surface receptor CCR5-high and CCR5-low cells and breast cancer stem cells, to predict the tumor growth rate and spatio-temporal distribution of cells in primary tumors. We find that high cancer stem cell percentages greatly increase tumor growth. We find that anti-stem cell treatment decreases tumor growth but may not lead to dormancy unless all stem cells get eliminated. We further find that hypoxia increases overall tumor growth and treatment with a CCR5 inhibitor maraviroc slightly decreases overall tumor growth. We also characterize 3D shapes of solid and invasive tumors using several shape metrics. CONCLUSIONS: Breast cancer stem cells and CCR5+ cells affect the overall growth and morphology of breast tumors. In silico drug treatments demonstrate limited efficacy of incomplete inhibition of cancer stem cells after which tumor growth recurs, and CCR5 inhibition causes only a slight reduction in tumor growth.

Effects of endothelial cell proliferation and migration rates in a computational model of sprouting angiogenesis.

Angiogenesis, the recruitment of new blood vessels, is a critical process for the growth, expansion, and metastatic dissemination of developing tumors. Three types of cells make up the new vasculature: tip cells, which migrate in response to gradients of vascular endothelial growth factor (VEGF), stalk cells, which proliferate and extend the vessels, and phalanx cells, which are quiescent and support the sprout. In this study we examine the contribution of tip cell migration rate and stalk cell proliferation rate on the formation of new vasculature. We calculate several vascular metrics, such as the number of vascular bifurcations per unit volume, vascular segment length per unit volume, and vascular tortuosity. These measurements predict that proliferation rate has a greater effect on the spread and extent of vascular growth compared to migration rate. Together, these findings provide strong implications for designing anti-angiogenic therapies that may differentially target endothelial cell proliferation and migration. Computational models can be used to predict optimal anti-angiogenic therapies in combination with other therapeutics to improve outcome.

Heterogeneity of chemokine cell-surface receptor expression in triple-negative breast cancer.

INTRODUCTION: Tumor heterogeneity is a well-established concept in cancer research. In this paper, we examine an additional type of tumor cell heterogeneity - tumor cell-surface receptor heterogeneity. METHODS: We use flow cytometry to measure the frequency and numbers of cell-surface receptors on triple negative breast cancer cell lines. RESULTS: We find two distinct populations of human triple-negative breast cancer cells MDA-MB-231 when they are grown in culture, one with low surface levels of various chemokine receptors and a second with much higher levels. The population with high surface levels of these receptors is increased in the more metastatic MDA-MB-231-luc-d3h2ln cell line. CONCLUSION: We hypothesize that this high cell-surface receptor population is involved in metastasis. We find that the receptor high populations can be modulated by tumor conditioned media and IL6 treatment indicating that the tumor microenvironment is important for the maintenance and sizes of these populations.

Four-class classification of skin lesions with task decomposition strategy.

This paper proposes a new computer-aided method for the skin lesion classification applicable to both melanocytic skin lesions (MSLs) and nonmelanocytic skin lesions (NoMSLs). The computer-aided skin lesion classification has drawn attention as an aid for detection of skin cancers. Several researchers have developed methods to distinguish between melanoma and nevus, which are both categorized as MSL. However, most of these studies did not focus on NoMSLs such as basal cell carcinoma (BCC), the most common skin cancer and seborrheic keratosis (SK) despite their high incidence rates. It is preferable to deal with these NoMSLs as well as MSLs especially for the potential users who are not enough capable of diagnosing pigmented skin lesions on their own such as dermatologists in training and physicians with different expertise. We developed a new method to distinguish among melanomas, nevi, BCCs, and SKs. Our method calculates 828 candidate features grouped into three categories: color, subregion, and texture. We introduced two types of classification models: a layered model that uses a task decomposition strategy and flat models to serve as performance baselines. We tested our methods on 964 dermoscopy images: 105 melanomas, 692 nevi, 69 BCCs, and 98 SKs. The layered model outperformed the flat models, achieving detection rates of 90.48%, 82.51%, 82.61%, and 80.61% for melanomas, nevi, BCCs, and SKs, respectively. We also identified specific features effective for the classification task including irregularity of color distribution. The results show promise for enhancing the capability of the computer-aided skin lesion classification.

An agent-based model of cancer stem cell initiated avascular tumour growth and metastasis: the effect of seeding frequency and location.

It is very important to understand the onset and growth pattern of breast primary tumours as well as their metastatic dissemination. In most cases, it is the metastatic disease that ultimately kills the patient. There is increasing evidence that cancer stem cells are closely linked to the progression of the metastatic tumour. Here, we investigate stem cell seeding to an avascular tumour site using an agent-based stochastic model of breast cancer metastatic seeding. The model includes several important cellular features such as stem cell symmetric and asymmetric division, migration, cellular quiescence, senescence, apoptosis and cell division cycles. It also includes external features such as stem cell seeding frequency and location. Using this model, we find that cell seeding rate and location are important features for tumour growth. We also define conditions in which the tumour growth exhibits decremented and exponential growth patterns. Overall, we find that seeding, senescence and division limit affect not only the number of stem cells, but also their spatial and temporal distribution.

Antiangiogenic cancer drug sunitinib exhibits unexpected proangiogenic effects on endothelial cells.

Angiogenesis, the formation of new blood vessels, is an essential step for cancer progression, but antiangiogenic therapies have shown limited success. Therefore, a better understanding of the effects of antiangiogenic treatments on endothelial cells is necessary. In this study, we evaluate the changes in cell surface vascular endothelial growth factor receptor (VEGFR) expression on endothelial cells in culture treated with the antiangiogenic tyrosine kinase inhibitor drug sunitinib, using quantitative flow cytometry. We find that proangiogenic VEGFR2 cell surface receptor numbers are increased with sunitinib treatment. This proangiogenic effect might account for the limited effects of sunitinib as a cancer therapy. We also find that this increase is inhibited by brefeldin A, an inhibitor of protein transport from the endoplasmic reticulum to the Golgi apparatus. The complex dynamics of cell surface VEGFRs may be important for successful treatment of cancer with antiangiogenic therapeutics.

Automated reconstruction algorithm for identification of 3D architectures of cribriform ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is a pre-invasive carcinoma of the breast that exhibits several distinct morphologies but the link between morphology and patient outcome is not clear. We hypothesize that different mechanisms of growth may still result in similar 2D morphologies, which may look different in 3D. To elucidate the connection between growth and 3D morphology, we reconstruct the 3D architecture of cribriform DCIS from resected patient material. We produce a fully automated algorithm that aligns, segments, and reconstructs 3D architectures from microscopy images of 2D serial sections from human specimens. The alignment algorithm is based on normalized cross correlation, the segmentation algorithm uses histogram equilization, Otsu's thresholding, and morphology techniques to segment the duct and cribra. The reconstruction method combines these images in 3D. We show that two distinct 3D architectures are indeed found in samples whose 2D histological sections are similarly identified as cribriform DCIS. These differences in architecture support the hypothesis that luminal spaces may form due to different mechanisms, either isolated cell death or merging fronds, leading to the different architectures. We find that out of 15 samples, 6 were found to have 'bubble-like' cribra, 6 were found to have 'tube-like' criba and 3 were 'unknown.' We propose that the 3D architectures found, 'bubbles' and 'tubes', account for some of the heterogeneity of the disease and may be prognostic indicators of different patient outcomes.

Three-phase general border detection method for dermoscopy images using non-uniform illumination correction.

BACKGROUND: Computer-aided diagnosis of dermoscopy images has shown great promise in developing a quantitative, objective way of classifying skin lesions. An important step in the classification process is lesion segmentation. Many studies have been successful in segmenting melanocytic skin lesions (MSLs), but few have focused on non-melanocytic skin lesions (NoMSLs), as the wide variety of lesions makes accurate segmentation difficult. METHODS: We developed an automatic segmentation program for detecting borders of skin lesions in dermoscopy images. The method consists of a pre-processing phase, general lesion segmentation phase, including illumination correction, and bright region segmentation phase. RESULTS: We tested our method on a set of 107 NoMSLs and a set of 319 MSLs. Our method achieved precision/recall scores of 84.5% and 88.5% for NoMSLs, and 93.9% and 93.8% for MSLs, in comparison with manual extractions from four or five dermatologists. CONCLUSION: The accuracy of our method was competitive or better than five recently published methods. Our new method is the first method for detecting borders of both non-melanocytic and melanocytic skin lesions.

Development of a novel border detection method for melanocytic and non-melanocytic dermoscopy images.

Computer aided diagnosis of dermoscopy images has shown great promise in developing a quantitative, objective way of classifying skin lesions. An important step in the classification process is the lesion segmentation. Many papers have been successful at segmenting melanocytic skin lesions (MSLs) but few have focused on non-melanocytic skin lesions (NoMSLs), since the wide variety of lesions makes accurate segmentation difficult. We developed an automatic segmentation program for the border detection of skin lesions. We tested our method on a set of 107 non-melanocytic lesions and on a set of 319 melanocytic lesions. Our method achieved precision/recall scores of 84.5% and 88.5% for NoMSLs, achieving higher scores than two previously published methods. Our method also achieved precision/recall scores of 93.9% and 93.8% for MSLs which was competitive or better than the two other methods. Therefore, we conclude that our approach is an accurate segmentation method for both melanocytic and non-melanocytic lesions.

Classification of melanocytic skin lesions from non-melanocytic lesions.

In this paper, we present a classification method of dermoscopy images between melanocytic skin lesions (MSLs) and non-melanocytic skin lesions (NoMSLs). The motivation of this research is to develop a pre-processor of an automated melanoma screening system. Since NoMSLs have a wide variety of shapes and their border is often ambiguous, we developed a new tumor area extraction algorithm to account for these difficulties. We confirmed that this algorithm is capable of handling different dermoscopy images not only those of NoMSLs but also MSLs as well. We determined the tumor area from the image using this new algorithm, calculated a total 428 features from each image, and built a linear classifier. We found only two image features, "the skewness of bright region in the tumor along its major axis" and "the difference between the average intensity in the peripheral part of the tumor and that in the normal skin area using the blue channel" were very efficient at classifying NoMSLs and MSLs. The detection accuracy of MSLs by our classifier using only the above mentioned image feature has a sensitivity of 98.0% and a specificity of 86.6% in a set of 107 non-melanocytic and 548 melanocytic dermoscopy images using a cross-validation test.

Skin lesion segmentation using an improved snake model.

Accurate identification of lesion borders is an important task in the analysis of dermoscopy images since the extraction of skin lesion borders provides important cues for accurate diagnosis. Snakes have been used for segmenting a variety of medical imagery including dermoscopy, however, due to the compromise of internal and external energy forces they can lead to under- or over-segmentation problems. In this paper, we introduce a mean shift based gradient vector flow (GVF) snake algorithm that drives the internal/external energies towards the correct direction. The proposed segmentation method incorporates a mean shift operation within the standard GVF cost function. Experimental results on a large set of diverse dermoscopy images demonstrate that the presented method accurately determines skin lesion borders in dermoscopy images.

A 2D mechanistic model of breast ductal carcinoma in situ (DCIS) morphology and progression.

Ductal carcinoma in situ (DCIS) of the breast is a non-invasive tumor in which cells proliferate abnormally, but remain confined within a duct. Although four distinguishable DCIS morphologies are recognized, the mechanisms that generate these different morphological classes remain unclear, and consequently the prognostic strength of DCIS classification is not strong. To improve the understanding of the relation between morphology and time course, we have developed a 2D in silico particle model of the growth of DCIS within a single breast duct. This model considers mechanical effects such as cellular adhesion and intra-ductal pressure, and biological features including proliferation, apoptosis, necrosis, and cell polarity. Using this model, we find that different regions of parameter space generate distinct morphological subtypes of DCIS, so elucidating the relation between morphology and time course. Furthermore, we find that tumors with similar architectures may in fact be produced through different mechanisms, and we propose future work to further disentangle the mechanisms involved in DCIS progression.