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Abstract
Cellular plasticity during cancer metastasis is a major clinical challenge. Two key cellular plasticity mechanisms —Epithelial-to-Mesenchymal Transition (EMT) and Mesenchymal-to-Amoeboid Transition (MAT) – have been carefully investigated individually, yet a comprehensive understanding of their interconnections remains elusive. Previously, we have modeled the dynamics of the core regulatory circuits for both EMT (miR-200/ZEB/miR-34/SNAIL) and MAT (Rac1/RhoA). We now extend our previous work to study the coupling between these two core circuits by considering the two microRNAs (miR-200 and miR-34) as external signals to the core MAT circuit. We show that this coupled circuit enables four different stable steady states (phenotypes) that correspond to hybrid epithelial/mesenchymal (E/M), mesenchymal (M), amoeboid (A) and hybrid amoeboid/mesenchymal (A/M) phenotypes. Our model recapitulates the metastasis-suppressing role of the microRNAs even in the presence of EMT-inducing signals like Hepatocyte Growth Factor (HGF). It also enables mapping the microRNA levels to the transitions among various cell migration phenotypes. Finally, it offers a mechanistic understanding for the observed phenotypic transitions among different cell migration phenotypes, specifically the Collective-to-Amoeboid Transition (CAT).
Highlights
Metastasis causes more than 90% of cancer-related deaths[1]
The core regulatory circuit consists of two interconnected mutually inhibitory circuits between a microRNA and a transcription factor (TF) – miR-34/SNAIL and miR-200/ ZEB4 (Fig. 1a). miR-34/SNAIL acts as an integrator of various external signals for inducing or inhibiting Epithelial–to-Mesenchymal Transition (EMT), and feeds to miR-200/ZEB that acts as the three-way decision making switch for EMT/Mesenchymal-to-Epithelial Transition (MET), thereby allowing for three distinct phenotypes – E, M and E/M15
Our results further indicate that the high levels of microRNAs, miR-200 and miR-34, can restrict the transitions towards solitary migration phenotypes, even in the presence of EMT-stimulating signals, such as Hepatocyte Growth Factor (HGF)
Summary
Metastasis causes more than 90% of cancer-related deaths[1]. For carcinomas, the most common type of tumors, metastasis begins when some epithelial cells from the primary tumor lose their apico-basal polarity and cell-cell adhesion and acquire migratory and invasive characteristics, through a process known as Epithelial–to-Mesenchymal Transition (EMT)[2]. Cells can undergo a partial or complete EMT and move collectively or individually while treading through the extra-cellular matrix (ECM) and circulating in the bloodstream[3,4]. Cancer cells can switch from A to M phenotype or vice-versa by undergoing an Ameoboid-to-Mesenchymal Transition (AMT) or a Mesenchymal-to-Amoeboid www.nature.com/scientificreports/. Migrating cells in E/M phenotype can switch to individually migrating cells in M phenotype or vice-versa during EMT4. Our previous theoretical work has explained how the core EMT/MET regulatory circuit allows transitions between E/M phenotype displaying collective cell migration and the mesenchymal (M) phenotype displaying individual migration[15]. Our previous work has elucidated how the core AMT/ MAT regulatory circuit enables for transitions among the three modes of individual migration – A, M and hybrid A/M14. High levels of active RhoA (or RhoA-GTP) correspond to amoeboid phenotype (A)[5], high levels of active Rac[1] (or Rac1-GTP) correspond to mesenchymal phenotype (M)[5], and both high levels of active Rac[1] and RhoA correspond to hybrid amoeboid/mesenchymal (A/M) phenotype[14]
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