Coupled mutual inhibition and mutual activation motifs as tools for cell-fate control.

Multistability is central to biological systems as it plays a crucial role in adaptation, evolvability, and differentiation. The presence of positive feedback loops can enable multistability. The simplest of such feedback loops are a) a mutual inhibition loop (MI), b) a mutual activation loop (MA), and c) self-activation, all three of them known to give rise to bistability. However, the characteristic differences in the bistability exhibited by these motifs are relatively less understood. Here, we use dynamical simulations across a large ensemble of parameter sets and initial conditions to study the bistability characteristics of these motifs. Furthermore, we investigate the utility of these motifs for achieving coordinated expression through cyclic and parallel coupling amongst them. Our analysis revealed that MI-based architectures offer discrete and robust control over gene expression, multistability, and coordinated expression among multiple genes, as compared to MA-based architectures. We then devised a combination of MI and MA architectures to improve coordination and multistability. Such designs help improve our understanding of the control structures involved in robust cell-fate decisions and provide a way to achieve controlled decision-making in synthetic systems.

Erratum: Iyer, A., et al. Integrative Analysis and Machine Learning Based Characterization of Single Circulating Tumor Cells. J. Clin. Med. 2020, 9, 1206.

In the published manuscript [...].

Author Correction: Identifying inhibitors of epithelial-mesenchymal plasticity using a network topology-based approach.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Identifying inhibitors of epithelial-mesenchymal plasticity using a network topology-based approach.

Metastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial-mesenchymal plasticity (EMP)-an important arm of phenotypic plasticity-through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis-by reducing the number of positive feedback loops.

Integrative Analysis and Machine Learning based Characterization of Single Circulating Tumor Cells.

We collated publicly available single-cell expression profiles of circulating tumor cells (CTCs) and showed that CTCs across cancers lie on a near-perfect continuum of epithelial to mesenchymal (EMT) transition. Integrative analysis of CTC transcriptomes also highlighted the inverse gene expression pattern between PD-L1 and MHC, which is implicated in cancer immunotherapy. We used the CTCs expression profiles in tandem with publicly available peripheral blood mononuclear cell (PBMC) transcriptomes to train a classifier that accurately recognizes CTCs of diverse phenotype. Further, we used this classifier to validate circulating breast tumor cells captured using a newly developed microfluidic system for label-free enrichment of CTCs.