Abstract
Melanoma is one of the most aggressive and highly resistant tumors. Cell plasticity in melanoma is one of the main culprits behind its metastatic capabilities. The detailed molecular mechanisms controlling melanoma plasticity are still not completely understood. Here we combine mathematical models of phenotypic switching with experiments on IgR39 human melanoma cells to identify possible key targets to impair phenotypic switching. Our mathematical model shows that a cancer stem cell subpopulation within the tumor prevents phenotypic switching of the other cancer cells. Experiments reveal that hsa-mir-222 is a key factor enabling this process. Our results shed new light on melanoma plasticity, providing a potential target and guidance for therapeutic studies.
Highlights
Plasticity of tumor cells is a key ingredient of tumor growth and a critical step for developing a successful anti-tumor therapy
We developed a mean-field model in which cancer stem cells (CSCs) are capable of unlimited proliferation [1,23], while cancer cells (CCs) can only divide into two CCs for a limited number g of generations, after which they become senescent and die
The model was used to generate the dynamical behavior of the number S of CSCs, of the number Nj of CCs with various age j, of the total number N = ∑ig=0 Ni of CCs and of the number m of inhibitor molecules
Summary
Plasticity of tumor cells is a key ingredient of tumor growth and a critical step for developing a successful anti-tumor therapy. Our group showed that a network of miRNAs modulates phenotypic switching in human melanoma through Wnt signalling and epithelial–mesenchymal transition (EMT) in human melanoma cells, controlling the total number of cancer stem cells (CSCs) in the tumor [1]. If for some reason a drastic depletion of SCs occurs, other more differentiated cells can revert to the SC state, replenishing the population During this process, the CSCs subpopulation overshoots to a concentration higher than the original one and returns to the initial level. Recent work showed that microenvironmental signals [13] and the density of the extracellular matrix [14] modulate the spatial patterning of CSCs. One of the important consequences of tumor plasticity lies in its impact on drug treatment [15]. A recent paper showed that after continuous drug treatment, slow-cycling melanoma cells enriched within the tumor show a SC-like phenotype [16]
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