Abstract
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. Our results show how different coupling strengths between AR and EMT signaling can lead to monostability, bistability, or oscillations in the levels of AR, as well as propagation of oscillations to EMT dynamics. These results reveal the emergent dynamics of coupled oscillatory and multi-stable systems and unravel mechanisms by which non-genetic heterogeneity in AR levels can be generated, which can act as a barrier to most existing therapies for prostate cancer patients.
Highlights
Phenotypic plasticity, i.e., the ability of cells to switch back and forth reversibly among different states, is a universal feature of adaptation to varying environments encountered by various biological systems [1]
The PAGE4-AR circuit consists of three relevant PAGE4 phospho-forms (WT-PAGE4, HIPK1-PAGE4, CLK2-PAGE4), together with c-Jun and androgen receptor (AR)
We investigated the dynamics of this extended circuit at varied strengths of coupling between AR and X, and different strengths of interaction in PAGE4-AR feedback loop
Summary
Phenotypic plasticity, i.e., the ability of cells to switch back and forth reversibly among different states (phenotypes), is a universal feature of adaptation to varying environments encountered by various biological systems [1]. This theme has been investigated in developmental and evolutionary biology in detail [2,3], and is gaining importance in the context of disease progression as well [4,5,6,7]. Unlike genomic changes that are “hard-wired” and can be inherited by cell division, phenotypic
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