scholarly journals An interplay between reaction-diffusion and cell-matrix adhesion regulates multiscale invasion in early breast carcinomatosis

2019 ◽  
Author(s):  
Dharma Pally ◽  
Durjay Pramanik ◽  
Ramray Bhat
Keyword(s):  
Computational Model ◽  
Cancer Cells ◽  
Experimental Model ◽  
Computational Models ◽  
Reaction Diffusion ◽  
Time Lapse ◽  
Matrix Remodeling ◽  
Cellular Potts Model ◽  
Relative Contribution ◽  
Cell Matrix

The progression of cancer in the breast involves multiple reciprocal interactions between malignantly transformed epithelia, surrounding untransformed but affected stromal cells, and the extracellular matrix (ECM) that is remodelled during the process. A quantitative understanding of the relative contribution of such interactions to phenotypes associated with cancer cells can be arrived at through the construction of increasingly complex experimental and computational models. Herein, we introduce a multiscale 3D organo-and patho-typic model that approximates, to an unprecedented extent, the histopathological complexity of a tumor disseminating into its surrounding stromal milieu via both bulk and solitary motility dynamics. End-point and time-lapse microscopic observations of this model allow us to study the earliest steps of cancer invasion as well as the dynamical interactions between the epithelial and stromal compartments. We then construct an agent-based Cellular Potts model that incorporates constituents of the experimental model, as well as places them in similar spatial arrangements. The computational model, which comprises adhesion between cancer cells and the matrices, cell proliferation and apoptosis, and matrix remodeling through reaction-diffusion-based morphogen dynamics, is first trained to phenocopy controls run with the experimental model, wherein one or the other matrices have been removed. The trained computational model successfully predicts phenotypes of the experimental counterparts that are subjected to pharmacological treatments (inhibition of N-linked glycosylation and matrix metalloproteinase activity) and scaffold modulation (alteration of collagen density). Our results suggest that specific permissive regimes of cell-cell and cell-matrix adhesions operating in the context of a reaction-diffusion-regulated ECM dynamics, promote multiscale invasion of breast cancer cells and determine the extent to which they migrate through their surrounding stroma.

scholarly journals On multiscale approaches to three-dimensional modelling of morphogenesis

2005 ◽  
Vol 2 (3) ◽  
pp. 237-253 ◽  
Author(s):  
R Chaturvedi ◽  
C Huang ◽  
B Kazmierczak ◽  
T Schneider ◽  
J.A Izaguirre ◽  
...  
Keyword(s):  
Computational Models ◽  
Genetic Regulation ◽  
Model Development ◽  
Three Dimensional ◽  
Reaction Diffusion ◽  
Cellular Potts Model ◽  
Reaction Diffusion Model ◽  
Current Implementation ◽  
Vertebrate Limb ◽  
Skeletal Pattern

In this paper we present the foundation of a unified, object-oriented, three-dimensional biomodelling environment, which allows us to integrate multiple submodels at scales from subcellular to those of tissues and organs. Our current implementation combines a modified discrete model from statistical mechanics, the Cellular Potts Model, with a continuum reaction–diffusion model and a state automaton with well-defined conditions for cell differentiation transitions to model genetic regulation. This environment allows us to rapidly and compactly create computational models of a class of complex-developmental phenomena. To illustrate model development, we simulate a simplified version of the formation of the skeletal pattern in a growing embryonic vertebrate limb.

scholarly journals Density-dependent migration characteristics of cancer cells driven by pseudopod coordination

2021 ◽  
Author(s):  
Gerhard A Burger ◽  
Bob van de Water ◽  
Sylvia E Le Dévédec ◽  
Joost B Beltman
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Single Cells ◽  
Cluster Formation ◽  
Time Lapse ◽  
Imaging Data ◽  
Cellular Potts Model ◽  
Primary Tumors ◽  
Density Dependent ◽  
Strong Cluster

The ability of cancer cells to invade neighboring tissue from primary tumors is an important determinant of metastatic behavior. Quantification of cell migration characteristics such as migration speed and persistence helps to understand the requirements for such invasiveness. One factor that may influence invasion is how local tumor cell density shapes cell migration characteristics, which we here investigate with a combined experimental and computational modeling approach. First, we generated and analyzed time-lapse imaging data on two aggressive Triple-Negative Breast Cancer (TNBC) cell lines, HCC38 and Hs578T, during 2D migration assays at various cell densities. HCC38 cells exhibited a counter-intuitive increase in speed and persistence with increasing density, whereas Hs578T did not exhibit such an increase. Moreover, HCC38 cells exhibited strong cluster formation with active pseudopod-driven migration, especially at low densities, whereas Hs578T cells maintained a dispersed positioning. In order to obtain a mechanistic understanding of the density-dependent cell migration characteristics and cluster formation, we developed realistic spatial simulations using a Cellular Potts Model (CPM) with an explicit description of pseudopod dynamics. Model analysis demonstrated that strong coordination between pseudopods within single cells could explain the experimentally observed increase in speed and persistence with increasing density in HCC38 cells. Thus, the density-dependent migratory behavior could be an emergent property of single-cell characteristics without the need for additional mechanisms. This implies that coordination amongst pseudopods may play a role in the aggressive nature of cancers through mediating dispersal.

CSBPI_Site：Multi-Information Sources of Features to RNA Binding Sites Prediction

2021 ◽  
Vol 15 ◽  
Author(s):  
Lichao Zhang ◽  
Zihong Huang ◽  
Liang Kong
Keyword(s):  
Computational Model ◽  
Binding Sites ◽  
Noncoding Rna ◽  
Computational Models ◽  
Information Sources ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Gradient Boosting ◽  
Position Information ◽  
Rna Binding Sites

Background: RNA-binding proteins establish posttranscriptional gene regulation by coordinating the maturation, editing, transport, stability, and translation of cellular RNAs. The immunoprecipitation experiments could identify interaction between RNA and proteins, but they are limited due to the experimental environment and material. Therefore, it is essential to construct computational models to identify the function sites. Objective: Although some computational methods have been proposed to predict RNA binding sites, the accuracy could be further improved. Moreover, it is necessary to construct a dataset with more samples to design a reliable model. Here we present a computational model based on multi-information sources to identify RNA binding sites. Method: We construct an accurate computational model named CSBPI_Site, based on xtreme gradient boosting. The specifically designed 15-dimensional feature vector captures four types of information (chemical shift, chemical bond, chemical properties and position information). Results: The satisfied accuracy of 0.86 and AUC of 0.89 were obtained by leave-one-out cross validation. Meanwhile, the accuracies were slightly different (range from 0.83 to 0.85) among three classifiers algorithm, which showed the novel features are stable and fit to multiple classifiers. These results showed that the proposed method is effective and robust for noncoding RNA binding sites identification. Conclusion: Our method based on multi-information sources is effective to represent the binding sites information among ncRNAs. The satisfied prediction results of Diels-Alder riboz-yme based on CSBPI_Site indicates that our model is valuable to identify the function site.

scholarly journals Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

2021 ◽  
Author(s):  
Stacey J. Scott ◽  
Xiaodun Li ◽  
Sriganesh Jammula ◽  
Ginny Devonshire ◽  
Catherine Lindon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Cell Biology ◽  
Time Lapse ◽  
Rna Seq ◽  
Cancer Evolution ◽  
Mitotic Slippage ◽  
Quantitative Immunofluorescence ◽  
Cancer Types ◽  
Eac Cells

AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

scholarly journals Numerical and Experimental Investigations on Vocal Fold Approximation in Healthy and Simulated Unilateral Vocal Fold Paralysis

2021 ◽  
Vol 11 (4) ◽  
pp. 1817
Author(s):  
Zheng Li ◽  
Azure Wilson ◽  
Lea Sayce ◽  
Amit Avhad ◽  
Bernard Rousseau ◽  
...  
Keyword(s):  
Computational Model ◽  
Vocal Fold ◽  
High Speed ◽  
Computational Models ◽  
Ex Vivo ◽  
Vocal Fold Paralysis ◽  
Future Application ◽  
Experimental Investigations ◽  
Type I ◽  
Mri Scans

We have developed a novel surgical/computational model for the investigation of unilat-eral vocal fold paralysis (UVFP) which will be used to inform future in silico approaches to improve surgical outcomes in type I thyroplasty. Healthy phonation (HP) was achieved using cricothyroid suture approximation on both sides of the larynx to generate symmetrical vocal fold closure. Following high-speed videoendoscopy (HSV) capture, sutures on the right side of the larynx were removed, partially releasing tension unilaterally and generating asymmetric vocal fold closure characteristic of UVFP (sUVFP condition). HSV revealed symmetric vibration in HP, while in sUVFP the sutured side demonstrated a higher frequency (10–11%). For the computational model, ex vivo magnetic resonance imaging (MRI) scans were captured at three configurations: non-approximated (NA), HP, and sUVFP. A finite-element method (FEM) model was built, in which cartilage displacements from the MRI images were used to prescribe the adduction, and the vocal fold deformation was simulated before the eigenmode calculation. The results showed that the frequency comparison between the two sides was consistent with observations from HSV. This alignment between the surgical and computational models supports the future application of these methods for the investigation of treatment for UVFP.

scholarly journals Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Bruno Sarmento ◽  
Hassan Bousbaa
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Antimitotic Drugs ◽  
Mitotic Slippage ◽  
Mitotic Death ◽  
Chronic Activation

AbstractAntimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31comet, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31comet, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31comet-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31comet as a target for antimitotic therapies.

scholarly journals CircPVT1 attenuates negative regulation of NRAS by let-7 and drives cancer cells towards oncogenicity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joshua Miguel C. Danac ◽  
Reynaldo L. Garcia
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rnas ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Relative Contribution ◽  
Colorectal Cancer Cells ◽  
Migration Resistance ◽  
Global Action ◽  
A549 Lung

AbstractCircular RNAs have emerged as functional regulatory molecules whose aberrant expression has been linked to diverse pathophysiological processes. Here, we report that circPVT1 interferes with let-7 binding to NRAS, confirming this axis as one route by which circPVT1 can instigate an oncogenic program in A549 lung cancer cells and HCT116 colorectal cancer cells. CircPVT1 knockdown significantly reduced NRAS levels and attenuated cancer hallmark phenotypes such as proliferation, migration, resistance to apoptosis, cytoskeletal disorganization, and epithelial-mesenchymal transition. The effects of circPVT1 knockdown were at least partially rescued by blocking binding of let-7 to NRAS 3′UTR with a target protector, suggesting that a circPVT1/let-7/NRAS axis exists and acts in cells to reverse NRAS downregulation and favor oncogenicity. While the phenotypic effects of circPVT1 knockdown may be attributable to the global action of circPVT1, the target protection assays resolved the relative contribution of the circPVT1/let-7/NRAS axis specifically.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals An Experimental Model of Breast Cancer Cells: Informative Protocol for In Vitro Culture

2018 ◽  
Vol 38 (11) ◽  
pp. 6237-6245 ◽  
Author(s):  
XINXIN DU ◽  
KRISTINA KLASCHIK ◽  
PETER MALLMANN ◽  
EVGENIA ISACHENKO ◽  
GOHAR RAHIMI ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Vitro Culture ◽  
Cancer Cells ◽  
Experimental Model ◽  
Breast Cancer Cells

scholarly journals Actin-inspired feedback couples speed and persistence in a Cellular Potts Model of cell migration

2018 ◽  
Author(s):  
Inge M. N. Wortel ◽  
Ioana Niculescu ◽  
P. Martijn Kolijn ◽  
Nir Gov ◽  
Rob J. de Boer ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Motility ◽  
Potts Model ◽  
Cell Shape ◽  
Computational Models ◽  
Fundamental Property ◽  
Cellular Potts Model ◽  
Universal Coupling ◽  
Migrating Cells

ABSTRACTCell migration is astoundingly diverse. Molecular signatures, cell-cell and cell-matrix interactions, and environmental structures each play their part in shaping cell motion, yielding numerous different cell morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently. Given this universal coupling between speed and persistence (UCSP), from a modelling perspective it is important to know whether computational models of cell migration capture this speed-persistence link. Here, we present an in-depth characterisation of an existing Cellular Potts Model (CPM). We first show that this model robustly reproduces the UCSP without having been designed for this task. Instead, we show that this fundamental law of migration emerges spontaneously through a crosstalk of intracellular mechanisms, cell shape, and environmental constraints, resembling the dynamic nature of cell migration in vivo. Our model also reveals how cell shape dynamics can further constrain cell motility by limiting both the speed and persistence a cell can reach, and how a rigid environment such as the skin can restrict cell motility even further. Our results further validate the CPM as a model of cell migration, and shed new light on the speed-persistence coupling that has emerged as a fundamental property of migrating cells.SIGNIFICANCEThe universal coupling between speed and persistence (UCSP) is the first general quantitative law describing motility patterns across the versatile spectrum of migrating cells. Here, we show – for the first time – that this migration law emerges spontaneously in an existing, highly popular computational model of cell migration. Studying the UCSP in entirely different model frameworks, not explicitly built with this law in mind, can help uncover how intracellular dynamics, cell shape, and environment interact to produce the diverse motility patterns observed in migrating cells.

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