Spatial transition tensor of single cells.

Spatial transcriptomics and messenger RNA splicing encode extensive spatiotemporal information for cell states and transitions. The current lineage-inference methods either lack spatial dynamics for state transition or cannot capture different dynamics associated with multiple cell states and transition paths. Here we present spatial transition tensor (STT), a method that uses messenger RNA splicing and spatial transcriptomes through a multiscale dynamical model to characterize multistability in space.

Tipping points in epithelial-mesenchymal lineages from single-cell transcriptomics data.

Understanding cell fate decision-making during complex biological processes is an open challenge that is now aided by high-resolution single-cell sequencing technologies. Specifically, it remains challenging to identify and characterize transition states corresponding to "tipping points" whereby cells commit to new cell states. Here, we present a computational method that takes advantage of single-cell transcriptomics data to infer the stability and gene regulatory networks (GRNs) along cell lineages.

Spatial-temporal order-disorder transition in angiogenic NOTCH signaling controls cell fate specification.

Angiogenesis is a morphogenic process resulting in the formation of new blood vessels from pre-existing ones, usually in hypoxic micro-environments. The initial steps of angiogenesis depend on robust differentiation of oligopotent endothelial cells into the Tip and Stalk phenotypic cell fates, controlled by NOTCH-dependent cell-cell communication. The dynamics of spatial patterning of this cell fate specification are only partially understood.

Theoretical and computational tools to model multistable gene regulatory networks.

The last decade has witnessed a surge of theoretical and computational models to describe the dynamics of complex gene regulatory networks, and how these interactions can give rise to multistable and heterogeneous cell populations. As the use of theoretical modeling to describe genetic and biochemical circuits becomes more widespread, theoreticians with mathematical and physical backgrounds routinely apply concepts from statistical physics, non-linear dynamics, and network theory to biological systems. This review aims at providing a clear overview of the most important methodologies applied in the field while highlighting current and future challenges.

Putting the Gaming Experience at the Center of the Therapy-The Video Game Therapy Approach.

Video games have been increasingly used as a form of therapy for various mental health conditions. Research has shown that video games can be used to treat conditions such as depression, anxiety, PTSD, and addiction. One of the main benefits of video games in therapy is that they can provide a sense of engagement and immersion that traditional therapy methods may lack.

Theoretical and computational tools to model multistable gene regulatory networks.

The last decade has witnessed a surge of theoretical and computational models to describe the dynamics of complex gene regulatory networks, and how these interactions can give rise to multistable and heterogeneous cell populations. As the use of theoretical modeling to describe genetic and biochemical circuits becomes more widespread, theoreticians with mathematical and physical backgrounds routinely apply concepts from statistical physics, non-linear dynamics, and network theory to biological systems. This review aims at providing a clear overview of the most important methodologies applied in the field while highlighting current and future challenges.

Differential cell composition and split epidermal differentiation in human palm, sole, and hip skin.

Palmoplantar skin is structurally and functionally unique, but the transcriptional programs driving this specialization are unclear. Here, we use bulk and single-cell RNA sequencing of human palm, sole, and hip skin to describe the distinguishing characteristics of palmoplantar and non-palmoplantar skin while also uncovering differences between palmar and plantar sites. Our approach reveals an altered immune environment in palmoplantar skin, with downregulation of diverse immunological processes and decreased immune cell populations.

spliceJAC: transition genes and state-specific gene regulation from single-cell transcriptome data.

Extracting dynamical information from single-cell transcriptomics is a novel task with the promise to advance our understanding of cell state transition and interactions between genes. Yet, theory-oriented, bottom-up approaches that consider differences among cell states are largely lacking. Here, we present spliceJAC, a method to quantify the multivariate mRNA splicing from single-cell RNA sequencing (scRNA-seq).

Stochastic fluctuations promote ordered pattern formation of cells in the Notch-Delta signaling pathway.

The Notch-Delta signaling pathway mediates cell differentiation implicated in many regulatory processes including spatiotemporal patterning in tissues by promoting alternate cell fates between neighboring cells. At the multicellular level, this "lateral inhibition" principle leads to checkerboard patterns with alternation of Sender and Receiver cells. While it is well known that stochasticity modulates cell fate specification, little is known about how stochastic fluctuations at the cellular level propagate during multicell pattern formation.

Nrf2 Modulates the Hybrid Epithelial/Mesenchymal Phenotype and Notch Signaling During Collective Cancer Migration.

Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process.

Single-Cell RNA-Seq Analysis Reveals the Acquisition of Cancer Stem Cell Traits and Increase of Cell-Cell Signaling during EMT Progression.

Intermediate cell states (ICSs) during the epithelial-mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell-cell signaling.

Decoding leader cells in collective cancer invasion.

Collective cancer invasion with leader-follower organization is increasingly recognized as a predominant mechanism in the metastatic cascade. Leader cells support cancer invasion by creating invasion tracks, sensing environmental cues and coordinating with follower cells biochemically and biomechanically. With the latest developments in experimental and computational models and analysis techniques, the range of specific traits and features of leader cells reported in the literature is rapidly expanding.

Coupled Feedback Loops Involving PAGE4, EMT and Notch Signaling Can Give Rise to Non-genetic Heterogeneity in Prostate Cancer Cells.

Non-genetic heterogeneity is emerging as a crucial factor underlying therapy resistance in multiple cancers. However, the design principles of regulatory networks underlying non-genetic heterogeneity in cancer remain poorly understood. Here, we investigate the coupled dynamics of feedback loops involving (a) oscillations in androgen receptor (AR) signaling mediated through an intrinsically disordered protein PAGE4, (b) multistability in epithelial-mesenchymal transition (EMT), and c) Notch-Delta-Jagged signaling mediated cell-cell communication, each of which can generate non-genetic heterogeneity through multistability and/or oscillations.

Inference of Intercellular Communications and Multilayer Gene-Regulations of Epithelial-Mesenchymal Transition From Single-Cell Transcriptomic Data.

Epithelial-to-mesenchymal transition (EMT) plays an important role in many biological processes during development and cancer. The advent of single-cell transcriptome sequencing techniques allows the dissection of dynamical details underlying EMT with unprecedented resolution. Despite several single-cell data analysis on EMT, how cell communicates and regulates dynamics along the EMT trajectory remains elusive.

Understanding the Principles of Pattern Formation Driven by Notch Signaling by Integrating Experiments and Theoretical Models.

Notch signaling is an evolutionary conserved cell-cell communication pathway. Besides regulating cell-fate decisions at an individual cell level, Notch signaling coordinates the emergent spatiotemporal patterning in a tissue through ligand-receptor interactions among transmembrane molecules of neighboring cells, as seen in embryonic development, angiogenesis, or wound healing. Due to its ubiquitous nature, Notch signaling is also implicated in several aspects of cancer progression, including tumor angiogenesis, stemness of cancer cells and cellular invasion.

Pericytes enable effective angiogenesis in the presence of proinflammatory signals.

Angiogenesis frequently occurs in the context of acute or persistent inflammation. The complex interplay of proinflammatory and proangiogenic cues is only partially understood. Using an experimental model, permitting exposure of developing blood vessel sprouts to multiple combinations of diverse biochemical stimuli and juxtacrine cell interactions, we present evidence that a proinflammatory cytokine, tumor necrosis factor (TNF), can have both proangiogenic and antiangiogenic effects, depending on the dose and the presence of pericytes.

A Biophysical Model Uncovers the Size Distribution of Migrating Cell Clusters across Cancer Types.

Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood.

NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype.

The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) - the prevalent mode of metastasis.

Quantifying Cancer Epithelial-Mesenchymal Plasticity and its Association with Stemness and Immune Response.

Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor.

Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level.

Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions.

Quantitative Characteristic of ncRNA Regulation in Gene Regulatory Networks.

RNA is mostly known for its role in protein synthesis, where it encodes information for protein sequence in its messenger RNA (mRNA) form (translation). Yet, RNA molecules regulate several cellular processes other than translation. Here, we present an overview of several mathematical models that help understanding and characterizing the role of noncoding RNA molecules (ncRNAs) in regulating gene expression and protein synthesis.

Toward understanding cancer stem cell heterogeneity in the tumor microenvironment.

The epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation are two paramount processes driving tumor progression, therapy resistance, and cancer metastasis. Recent experiments show that cells with varying EMT and CSC phenotypes are spatially segregated in the primary tumor. The underlying mechanisms generating such spatiotemporal dynamics in the tumor microenvironment, however, remain largely unexplored.

A mechanism-based computational model to capture the interconnections among epithelial-mesenchymal transition, cancer stem cells and Notch-Jagged signaling.

Epithelial-mesenchymal transition (EMT) and cancer stem cell (CSCs) formation are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose 'stemness'.

PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer.

Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein implicated in prostate cancer. Thestress-response kinase homeodomain-interacting protein kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with activator protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity.