RT Journal Article
SR Electronic
T1 A Rational Drug Combination Design Proves to Inhibit Epithelial-Mesenchymal Transition in a Three-Dimensional Microenvironment
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 148767
DO 10.1101/148767
A1 Farnaz Barneh
A1 Mehdi Mirzaie
A1 Payman Nickchi
A1 Mehran Piran
A1 Mona Salimi
A1 Fatemeh Goshadrou
A1 Amir Reza Aref
A1 Mohieddin Jafari
YR 2017
UL http://biorxiv.org/content/early/2017/06/12/148767.abstract
AB Epithelial-Mesenchymal Transition (EMT) is the major player of tumor invasiveness whose inhibition is challenged by redundancy of multiple inducing factors in tumor microenvironment. Here, we applied a systems pharmacology approach by integrating network-based analyses with multiple bioinformatic resources to propose a combinatorial drug regimen that reverses EMT phenotype in aggressive cancers. The results demonstrated that histone deacetylases were central targets to relay tumor-host interactions by tuning expression of multiple epithelial versus mesenchymal genes. Moreover, SRC and IKBK served as the principal intracellular kinases regulating information flow from tumor microenvironment to multiple signaling pathways associated with EMT. To experimentally validate these predictions, we inhibited the pinpointed targets with already prescribed drugs and observed that whereas low dose mono-therapy failed to limit cell dispersion in a three-dimensional (3D) microfluidic device as a metric of EMT, the combinatorial regimen fully inhibited dispersion and invasion of cancer cells in collagen spheroids toward co-cultured endothelial cells while maintaining their survival. Taking into account Food and Drug Administered (FDA) - approval as well as safety profiles of the proposed drugs, we offer a combinatorial regimen with immediate translational implications to inhibit EMT in aggressive cancers. Besides, our study provides a grasp on the interdisciplinary methodologies behind plethora of the introduced biologist-friendly bioinformatic tools for bench and bed cancer scientists to help them effectively plan their experiments.