Modulation of Network Plasticity Opens Novel Therapeutic Possibilities in Cancer, Diabetes, and Neurodegeneration.

Cellular plasticity is crucially important in cancer-induced cell reprogramming, as well as in regeneration therapies in diabetes, Alzheimer's, and Parkinson's diseases. Protein-protein interaction, signaling, and gene regulatory networks are increasingly used to describe plasticity-induced cellular adaptation in disease progression. This review delineates how network analysis of cell plasticity leads to novel therapy options against 1) cancer progression; 2) epithelial-mesenchymal transition-induced metastases; 3) cancer stem cells, and 4) pre-existent drug-resistant cells. Network plasticity-designed sequential and differentiation therapies are also outlined. 55 plasticity-related cancer drug targets are listed, where 20 have already approved drugs, 9 have investigational drugs, and 26 are drug target candidates. The recent expansion of plastic network-driven pancreatic beta cell and neuron regeneration therapies is described in diabetes, as well as in Alzheimer's and Parkinson's diseases, respectively. Finally, six major network-related research gaps and promising future research areas are outlined, including the discovery of plasticity-related cancer signaling pathways and cross-talks, cancer resensitization therapies, and the use of recently available proteome-wide network data and models to find novel cancer cell differentiation cocktails, drug targets, proper timing, and biomarkers of sequential therapies, as well as to perform in silico drug combination screens and in silico clinical trials.