Coordinators: C. Auclair (Partner 10) and R. Dodd (Partner 13)
Financial support from January 2012 until December 2014
Over 10 years ago, Partner 10 has initiated a new approach to understand cell cancer status by asking: how can a tumor cell escape from its malignant trajectory? Is there a specific signaling that will still allow a tumor cell to switch to at least a partial loss of its malignant potential with a subsequent suppression of its malignant phenotype?
Along this line, Partner 10 started in the past years a pharmacology program whose objective was to identify some specific molecular basis of malignant phenotype maintenance and ultimately the identification of key processes whose pharmacological manipulation would result in tumor phenotypic reversion. In agreement with previous observations, they hypothesized that the changes in the cytoskeletal architecture which is one of the main molecular mechanisms underlying tumor progression could be a pertinent target process and that pharmacological-induced actin network rearrangement may result in phenotypic reversion thanks to the rescue of adhesion and motility controls. This axis rests on the fundamental work developed earlier which has led Partner 10, thanks to a genomic approach, to the identification of a key gene (zyxin) for which the reduction in expression is directly responsible for the acquisition of the tumoral phenotype in the Ewing sarcoma model (see patent). The under-expression of this gene leads to a strong modification of the dynamics of actin polymerization resulting in a polarization of the cells, a loss of cell-cell membrane interactions, and an increase in the cellular motility. These observations have been the starting point of the development of a pharmacological project, whose objective is the identification of compounds able to reconstitute actin networks mainly in tumoral phenotypes which under-express zyxin (down regulation of zyxin is observed in various sarcomas, in melanoma and in leukemia such as AML and ALL). Actin cytoskeleton organization may as well modulate the anti-apoptotic status of tumor cells and one work package (WP) of the project will concern the study of the relations between the actin network architecture and sensitivity to ionizing radiation (Partner 8).
Based on the above considerations, we are in the process of identifying new antitumor drugs acting by a completely non-toxic process through the reversion of the tumoral phenotype. Along this line, molecular and functional screening procedures have allowed us to identify the β-carboline harmine as actin dynamics modulators resulting in the decrease of cell motility, the restoration of cell-cell adhesion and in fine the disappearance of the tumor phenotype. Through a pluridisciplinary endeavor involving five different partners (Partner 8, 10, 12, 13 & 15) and the technology platforms, this project aims at: 1) identifying the molecular target(s) of harmine and elucidating the mechanism of actin dynamics modulation (aim 1); 2) identifying organic molecules in the β-carboline series which restore actin cytoskeleton architecture in tumor cells leading to the decrease of cell motility and in the rescue of cell-cell adhesion properties (aim 2); 3) synthesizing new β-carboline derivatives and performing molecular optimization on the selected compounds (aim 3); 4) investigating the effect of actin dynamics modulators on the ionizing radiation efficiency (aim 4).