Unveiling unexpected tumor suppressor functions for Vav3 in nonsmall cell lung cancer
Speaker: Myriam Cuadrado
Centro de Investigación del Cáncer, CIC-IBMCC
Salón de actos del Centro de Investigación del Cáncer
Rho GTPases regulate a number of protumorigenic functions in cancer cells, including cytoskeletal organization, cell migration, proliferation, and cell survival. Consistent with this, a large plethora of cell- and animal model-based studies have shown that the elimination of most of these proteins contributes negatively to the fitness of cancer cells. Likewise, the recent characterization of the genome of cancer cells has revealed the presence at low frequency of gain-of-function mutations in some Rho GTPase-encoding genes such as, for example, RAC1.
Despite this, recent evidence indicates that some of these proteins can also regulate tumour suppression mechanisms. In line with this, loss-of-function and dominant negative mutations in Rho GTPases have been found in some tumour settings as well (e.g., RhoA). However, given that those mutations are found at low frequencies in patients, it is hypothesized that the wild-type counterparts are probably inhibited in cancer cells via alternative mechanisms.
In our lab, we have recently found using mouse models that Vav3, an enzyme that catalyses the activation step of Rho GTPases, unexpectedly plays tumour suppressor roles in non-small cell lung cancer (NSCLC). These data have been corroborated using a number of both mouse and human NSCLC cell lines. Further experiments have shown that this suppression pathway is RhoA-subfamily dependent. Perhaps more importantly, we have unveiled both the proximal and distal signalling elements that mediate this suppression mechanism. In addition to counteract cell proliferation, we have found that this pathway is also important for the regulation of the therapeutic responsiveness of NSCLC cells. Taken together, these data have unveiled a new, potentially therapeutically relevant signalling pathway involved in the suppression of KRAS-driven NSCLC. In addition, they have shed light into the hitherto elusive suppressor role of the RhoA subfamily in this tumour type.