Quantifying the underlying landscape and paths of cancer.
ABSTRACT: Cancer is a disease regulated by the underlying gene networks. The emergence of normal and cancer states as well as the transformation between them can be thought of as a result of the gene network interactions and associated changes. We developed a global potential landscape and path framework to quantify cancer and associated processes. We constructed a cancer gene regulatory network based on the experimental evidences and uncovered the underlying landscape. The resulting tristable landscape characterizes important biological states: normal, cancer and apoptosis. The landscape topography in terms of barrier heights between stable state attractors quantifies the global stability of the cancer network system. We propose two mechanisms of cancerization: one is by the changes of landscape topography through the changes in regulation strengths of the gene networks. The other is by the fluctuations that help the system to go over the critical barrier at fixed landscape topography. The kinetic paths from least action principle quantify the transition processes among normal state, cancer state and apoptosis state. The kinetic rates provide the quantification of transition speeds among normal, cancer and apoptosis attractors. By the global sensitivity analysis of the gene network parameters on the landscape topography, we uncovered some key gene regulations determining the transitions between cancer and normal states. This can be used to guide the design of new anti-cancer tactics, through cocktail strategy of targeting multiple key regulation links simultaneously, for preventing cancer occurrence or transforming the early cancer state back to normal state.
Project description:Cancer metabolism is critical for understanding the mechanism of tumorigenesis, yet the understanding is still challenging. We studied gene-metabolism regulatory interactions and quantified the global driving forces for cancer-metabolism dynamics as the underlying landscape and probability flux. We uncovered four steady-state attractors: a normal state attractor, a cancer OXPHOS state attractor, a cancer glycolysis state attractor, and an intermediate cancer state attractor. We identified the key regulatory interactions through global sensitivity analysis based on the landscape topography. Different landscape topographies of glycolysis switch between normal cells and cancer cells were identified. We uncovered that the normal state to cancer state transformation is associated with the peaks of the probability flux and the thermodynamic dissipation, giving dynamical and thermodynamic origin of cancer formation. We found that cancer metabolism oscillations consume more energy to support cancer malignancy. This study provides a quantitative understanding of cancer metabolism and suggests a metabolic therapeutic strategy.
Project description:Ageing is a natural phenomenon that is inherently complex and remains a mystery. Conceptual model of cellular ageing landscape was proposed for computational studies of ageing. However, there is a lack of quantitative model of cellular ageing landscape. This study aims to investigate the mechanism of cellular ageing in a theoretical model using the framework of Waddington's epigenetic landscape. We construct an ageing gene regulatory network (GRN) consisting of the core cell cycle regulatory genes (including p53). A model parameter (activation rate) is used as a measure of the accumulation of DNA damage. Using the bifurcation diagrams to estimate the parameter values that lead to multi-stability, we obtained a conceptual model for capturing three distinct stable steady states (or attractors) corresponding to homeostasis, cell cycle arrest, and senescence or apoptosis. In addition, we applied a Monte Carlo computational method to quantify the potential landscape, which displays: I) one homeostasis attractor for low accumulation of DNA damage; II) two attractors for cell cycle arrest and senescence (or apoptosis) in response to high accumulation of DNA damage. Using the Waddington's epigenetic landscape framework, the process of ageing can be characterized by state transitions from landscape I to II. By in silico perturbations, we identified the potential landscape of a perturbed network (inactivation of p53), and thereby demonstrated the emergence of a cancer attractor. The simulated dynamics of the perturbed network displays a landscape with four basins of attraction: homeostasis, cell cycle arrest, senescence (or apoptosis) and cancer. Our analysis also showed that for the same perturbed network with low DNA damage, the landscape displays only the homeostasis attractor. The mechanistic model offers theoretical insights that can facilitate discovery of potential strategies for network medicine of ageing-related diseases such as cancer.
Project description:Genome-wide regulatory networks enable cells to function, develop, and survive. Perturbation of these networks can lead to appearance of a disease phenotype. Inspired by Conrad Waddington's epigenetic landscape of cell development, we use a Hopfield network formalism to construct an attractor landscape model of disease progression based on protein- or gene-correlation networks of Parkinson's disease, glioma, and colorectal cancer. Attractors in this landscape correspond to normal and disease states of the cell. We introduce approaches to estimate the size and robustness of these attractors, and take a network-based approach to study their biological features such as the key genes and their functions associated with the attractors. Our results show that the attractor of cancer cells is wider than the attractor of normal cells, suggesting a heterogeneous nature of cancer. Perturbation analysis shows that robustness depends on characteristics of the input data (number of samples per time-point, and the fraction which converge to an attractor). We identify unique gene interactions at each stage, which reflect the temporal rewiring of the gene regulatory network (GRN) with disease progression. Our model of the attractor landscape, constructed from large-scale gene expression profiles of individual patients, captures snapshots of disease progression and identifies gene interactions specific to different stages, opening the way for development of stage-specific therapeutic strategies.
Project description:The epithelial-mesenchymal transition (EMT) is a basic developmental process that converts epithelial cells to mesenchymal cells. Although EMT might promote cancer metastasis, the molecular mechanisms for it remain to be fully clarified. To address this issue, we constructed an EMT-metastasis gene regulatory network model and quantified the potential landscape of cancer metastasis-promoting system computationally. We identified four steady-state attractors on the landscape, which separately characterize anti-metastatic (A), metastatic (M), and two other intermediate (I1 and I2) cell states. The tetrastable landscape and the existence of intermediate states are consistent with recent single-cell measurements. We identified one of the two intermediate states I1 as the EMT state. From a MAP approach, we found that for metastatic progression cells need to first undergo EMT (enter the I1 state), and then become metastatic (switch from the I1 state to the M state). Specifically, for metastatic progression, EMT genes (such as ZEB) should be activated before metastasis genes (such as BACH1). This suggests that temporal order is important for the activation of cellular programs in biological systems, and provides a possible mechanism of EMT-promoting cancer metastasis. To identify possible therapeutic targets from this landscape view, we performed sensitivity analysis for individual molecular factors, and identified optimal interventions for landscape control. We found that minimizing transition actions more effectively identifies optimal combinations of targets that induce transitions between attractors than single-factor sensitivity analysis. Overall, the landscape view not only suggests that intermediate states increase plasticity during cell fate decisions, providing a possible source for tumor heterogeneity that is critically important in metastatic progress, but also provides a way to identify therapeutic targets for preventing cancer progression.
Project description:Cancer is a disease governed by the underlying gene regulatory networks. The hallmarks of cancer have been proposed to characterize the cancerization, e.g., abnormal metabolism, epithelial to mesenchymal transition (EMT), and cancer metastasis. We constructed a metabolism-EMT-metastasis regulatory network and quantified its underlying landscape. We identified four attractors, characterizing epithelial, abnormal metabolic, mesenchymal, and metastatic cell states, respectively. Importantly, we identified an abnormal metabolic state. Based on the transition path theory, we quantified the kinetic transition paths among these different cell states. Our results for landscape and paths indicate that metastasis is a sequential process: cells tend to first change their metabolism, then activate the EMT and eventually reach the metastatic state. This demonstrates the importance of the temporal order for different gene circuits switching on or off during metastatic progression of cancer cells and underlines the cascading regulation of metastasis through an abnormal metabolic intermediate state.
Project description:<h4>Background</h4>Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far.<h4>Results</h4>To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals.<h4>Conclusions</h4>The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.
Project description:The study of the cancer-immune system is important for understanding tumorigenesis and the development of cancer and immunotherapy. In this work, we build a comprehensive cancer-immune model including both cells and cytokines to uncover the underlying mechanism of cancer immunity based on landscape topography. We quantify three steady-state attractors, normal state, low cancer state and high cancer state, for the innate immunity and adaptive immunity of cancer. We also illustrate the cardinal inhibiting cancer immunity interactions and promoting cancer immunity interactions through global sensitivity analysis. We simulate tumorigenesis and the development of cancer and classify these into six stages. The characteristics of the six stages can be classified further into three groups. These correspond to the escape, elimination and equilibrium phases in immunoediting, respectively. Under specific cell-cell interactions strength oscillations emerge. We found that tumorigenesis and cancer recovery processes may need to go through cancer-immune oscillation, which consumes more energy. Based on the cancer-immune landscape, we predict three types of cells and two types of cytokines for cancer immunotherapy as well as combination immunotherapy. This landscape framework provides a quantitative way to understand the underlying mechanisms of the interplay between cancer and the immune system for cancer tumorigenesis and development.
Project description:Initiation and progression of cancer depend on many factors. Those on the genetic level are often considered crucial. To gain insight into the physical mechanisms of breast cancer, we construct a gene regulatory network (GRN) which reflects both genetic and environmental aspects of breast cancer. The construction of the GRN is based on available experimental data. Three basins of attraction, representing the normal, premalignant and cancer states respectively, were found on the phenotypic landscape. The progression of breast cancer can be seen as switching transitions between different state basins. We quantified the stabilities and kinetic paths of the three state basins to uncover the biological process of breast cancer formation. The gene expression levels at each state were obtained, which can be tested directly in experiments. Furthermore, by performing global sensitivity analysis on the landscape topography, six key genes (HER2, MDM2, TP53, BRCA1, ATM, CDK2) and four regulations (HER2?TP53, CDK2?BRCA1, ATM?MDM2, TP53?ATM) were identified as being critical for breast cancer. Interestingly, HER2 and MDM2 are the most popular targets for treating breast cancer. BRCA1 and TP53 are the most important oncogene of breast cancer and tumor suppressor gene, respectively. This further validates the feasibility of our model and the reliability of our prediction results. The regulation ATM?MDM2 has been extensive studied on DNA damage but not on breast cancer. We notice the importance of ATM?MDM2 on breast cancer. Previous studies of breast cancer have often focused on individual genes and the anti-cancer drugs are mainly used to target the individual genes. Our results show that the network-based strategy is more effective on treating breast cancer. The landscape approach serves as a new strategy for analyzing breast cancer on both the genetic and epigenetic levels and can help on designing network based medicine for breast cancer.
Project description:Stem cell differentiation has been viewed as coming from transitions between attractors on an epigenetic landscape that governs the dynamics of a regulatory network involving many genes. Rigorous definition of such a landscape is made possible by the realization that gene regulation is stochastic, owing to the small copy number of the transcription factors that regulate gene expression and because of the single-molecule nature of the gene itself. We develop an approximation that allows the quantitative construction of the epigenetic landscape for large realistic model networks. Applying this approach to the network for embryonic stem cell development explains many experimental observations, including the heterogeneous distribution of the transcription factor Nanog and its role in safeguarding the stem cell pluripotency, which can be understood by finding stable steady-state attractors and the most probable transition paths between those attractors. We also demonstrate that the switching rate between attractors can be significantly influenced by the gene expression noise arising from the fluctuations of DNA occupancy when binding to a specific DNA site is slow.