Although fibroblasts are dormant in normal tissue, they exhibit explosive activation during wound healing and perpetual activation in pathologic fibrosis and cancer stroma. The key regulatory network controlling these fibroblast dynamics is still unknown. Here, we report that Twist1, a key regulator of cancer-associated fibroblasts, directly upregulates Prrx1, which, in turn, increases the expression of Tenascin-C (TNC). TNC also increases Twist1 expression, consequently forming a Twist1-Prrx1-TNC positive feedback loop (PFL). Systems biology studies reveal that the Twist1-Prrx1-TNC PFL can function as a bistable ON/OFF switch and regulates fibroblast activation. This PFL can be irreversibly activated under pathologic conditions, leading to perpetual fibroblast activation. Sustained activation of the Twist1-Prrx1-TNC PFL reproduces fibrotic nodules similar to idiopathic pulmonary fibrosis in vivo and is implicated in fibrotic disease and cancer stroma. Considering that this PFL is specific to activated fibroblasts, Twist1-Prrx1-TNC PFL may be a fibroblast-specific therapeutic target to deprogram perpetually activated fibroblasts.

Highlights d A computational neuronal circuit model of sensory cortex layers 2 and 3 is constructed d Cooperation of SST, VIP, and PV cells determines neuronal oscillation dynamics d The core structure regulating the top-down modulation of slow oscillation is found d The feedback between SST and VIP cells determines adaptability to top-down input

SummaryBiological oscillations are found ubiquitously in cells and are widely variable, with periods varying from milliseconds to months, and scales involving subcellular components to large groups of organisms. Interestingly, independent oscillators from different cells often show synchronization that is not the consequence of an external regulator. What is the underlying design principle of such synchronized oscillations, and can modeling show that the complex consequences arise from simple molecular or other interactions between oscillators? When biological oscillators are coupled with each other, we found that synchronization is induced when they are connected together through a positive feedback loop. Increasing the coupling strength of two independent oscillators shows a threshold beyond which synchronization occurs within a few cycles, and a second threshold where oscillation stops. The positive feedback loop can be composed of either double-positive (PP) or double-negative (NN) interactions between a node of each of the two oscillating networks. The different coupling structures have contrasting characteristics. In particular, PP coupling is advantageous with respect to stability of period and amplitude, when local oscillators are coupled with a short time delay, whereas NN coupling is advantageous for a long time delay. In addition, PP coupling results in more robust synchronized oscillations with respect to amplitude excursions but not period, with applied noise disturbances compared to NN coupling. However, PP coupling can induce a large fluctuation in the amplitude and period of the resulting synchronized oscillation depending on the coupling strength, whereas NN coupling ensures almost constant amplitude and period irrespective of the coupling strength. Intriguingly, we have also observed that artificial evolution of random digital oscillator circuits also follows this design principle. We conclude that a different coupling strategy might have been selected according to different evolutionary requirements. Journal of Cell Science 538other might account for cell-type-specific dynamic regulation. To unravel the most general design principles of synchronized oscillations, we focused on the positive feedback that couples two local oscillators. In general, positive feedback can amplify signals (Hasty et al., 2000), reduce a response speed, induce hysteresis (Becskei et al., 2001; Ferrell, 2002; Isaacs et al., 2003; Kim, J.-R. et al., 2008) and realize a toggle switch (Gardner et al., 2000; Hasty et al., 2000;Tyson et al., 2003; Kobayashi et al., 2004), but its role in coupling local independent oscillators and inducing synchronized oscillations has not been investigated yet.In this paper, we explore interesting and important features of the PP and NN feedback that couples two oscillators and enables synchronized oscillation. Through mathematical modeling and extensive computational simulations in which the strength of feedbacks coupling the two oscillators (coupling strength) and other parameters (inc...

Background: 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. Results: 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.

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