Systems Biology of Cancer Metastasis

Abstract

Cancer metastasis is no longer viewed as a linear cascade of events but rather as a series of concurrent, partially overlapping processes, as successfully metastasizing cells assume new phenotypes while jettisoning older behaviors. The lack of a systemic understanding of this complex phenomenon has limited progress in developing treatments for metastatic disease. Because metastasis has traditionally been investigated in distinct physiological compartments, the integration of these complex and interlinked aspects remains a challenge for both systems-level experimental and computational modeling of metastasis. Here, we present some of the current perspectives on the complexity of cancer metastasis, the multiscale nature of its progression, and a systems-level view of the processes underlying the invasive spread of cancer cells. We also highlight the gaps in our current understanding of cancer metastasis as well as insights emerging from interdisciplinary systems biology approaches to understand this complex phenomenon.

Mathematical modeling of metastasis, a feasible way to detect the weakness

“…Tumor cells with epithelial phenotype composing the tumor receive the signal of duplication through growth factors [27] . These cells begin to make the phenotype change due to external factors, such as the effect of the microenvironment [28] and/or interaction with the immune system [29] . In 2017 Takigawa et al [30] stated that mesenchymal stem cells induce epithelial to mesenchymal transition in colon cancer cells through direct cell-to-cell contact.…”

Cancer Stem Cell Plasticity – A Deadly Deal

“…With the deluge of preclinical and clinical data being generated at a high-dimensional level, computational approaches to extract meaningful information and generate testable hypotheses are becoming more common (Suhail et al, 2019). Various "topdown" and "bottom-up" computational methods provide a framework to unravel novel insights into various aspects of the dynamics of cancer progression such as role of intra-tumoral heterogeneity, dynamics of EMT, CSCs and its role in metastases, evolutionary dynamics of cancer initiation and progression, prediction of treatment response and therapy resistance (Figure 3).…”

Tuning Cancer Fate: Tumor Microenvironment's Role in Cancer Stem Cell Quiescence and Reawakening

“…Two-dimensional (2D) and three-dimensional (3D) cell cultures are the standard in vitro tools for investigating the mechanisms of cellular dormancy as well as the interactions with selected players of the microenvironment regulating major steps of dormancy such as cell cycle arrest, immunogenicity, differentiation, and therapeutic resistance. In the simplest 2D cell culture setting, cancer cells from either immortalized or primary cell lines are seeded on selected stromal components [e.g., fibronectin 1 (FN1), collagen I, collagen IV, among others] at clonogenic densities to favor cell interaction with the substratum and in the presence of microenvironmental Mechanistic modeling (82,83) Gene regulatory networks (84,85) Systems biology models (86) soluble factors [e.g., epidermal growth factor (EGF) and basic fibroblast growth factor]. The effect of such extracellular matrix (ECM) factors on cancer cell dormancy, survival, and metastatic potential can then be evaluated by analyzing (as examples) cell clonogenic potential upon staining with crystal violet or cancer cell morphology, phenotype, cell cycle arrest, proteome and transcriptome employing standard methods of cellular and molecular biology (e.g., by microscopy, flow cytometry, western blot, qRT-PCR, and other techniques) (44,45).…”

“…Mathematical oncology offers insights into the complexity and multiscale nature of cancer cell dormancy and dissemination, (i) by integrating experimental and clinical information (79-81), (ii) by mechanistically modeling tumor evolution and progression as a functional consequence of the complex interaction between cancer cells and the surrounding TME (82,83), and (iii) by predicting and simulating the molecular pathways involved (84,85). More recently, systems biology, a multidisciplinary approach that integrates cancer research and medicine, genetics and epigenetics, mathematics, physics, and bioinformatics has gained momentum in the study of cancer dormancy and reawakening, as provides a more comprehensive view of the dynamics of these complex processes (86).…”