L'inibizione della poli-ADP-ribosilasi tanchirasi compromette la migrazione direzionale e l'invasione di cellule di cancro del polmone interferendo con le dinamiche dei microtubuli e i segnali di polarità.

Tankyrases (TNKS) belong to the poly (ADP-ribose) polymerases (PARPs) family; their post-translational modulatory activity can positively or negatively affect targets stabilityby protecting them from or addressing them to proteasomal degradation TNKS activities are manifold and range from telomere homeostasis maintenance to proper spindle poles establishment during mitosis, vesicle trafficking and WNT pathway regulation. The establishment of polarized cell movement in response to chemotactic stimuli relies on a complex regulatory network: the presence of the small GTPase Cdc42 at the leading edge is required for adenomatous polyposis coli (APC) localization towards the cortical areas, through a kinesin-dependent transport to the plus ends of microtubules. APC clustering at protrusive sites preludes the polarization of the microtubule network and the consequent centrosome reorientation along the migration axis. The notion that tankyrases have versatile activities in processes that, when gone awry, invariably lead to aberrant cellular proliferation, has recently prompted the development of a number of specific and effective TNKS inhibitors Here we report a new function for tankyrases, namely, regulation of directional cell locomotion. The motogenic attractant hepatocyte growth factor (HGF) impacts the cytoskeleton to enhance the migratory tendency of cancer: using a panel of non-small cell lung cancer (NSCLC) cell lines as model system, we observed that TNKS inhibition results in mitigation of the HGF-induced invasive phenotype. We found that NSCLC cells treated with two structurally unrelated small-molecule inhibitors (one introduced and characterized here for the first time) or transduced with TNKS-specific shRNA experienced delayed wound closure in wound healing assays and failed polarisation of the TNKS abrogation impacts the dynamics underlying directional migration. Preliminary results allowed us to exclude the influence on proliferation-related events and the involvement WNT signalling. Thence, tankyrases appear to positively modulate directional migration through mechanisms that are not related to established tankyrase activities. Mechanistically, the anti-invasive outcome of tankyrase inhibition could be ascribed to sequential deterioration of the distinct events that govern cell directional sensing. In particular, we found that tankyrase blockade negatively impacted (1) microtubule dynamic instability; (2) APC plasma membrane targeting; and (3) centrosome reorientation. Collectively, these findings uncover an unanticipated role for tankyrases in influencing at multiple levels the interphase dynamics of the microtubule network and the subcellular distribution of related polarity signals. These results encourage the further exploration of tankyrase inhibitors as therapeutic tools to oppose dissemination and metastasis of cancer cells.