Resumen de tesis. Systematic analysis of RHO GTPases pathway alterations in cancer

Abstract

[EN]RHO GTPases are core signaling proteins involved in the regulation of different cell processes, such as cell survival, proliferation and migration, among others, that are essential for tumor cells acquisition of cancer hallmarks. Most of these proteins are molecular switches tightly regulated by three subfamilies of proteins. The RHO GEFs promote the exchange of GDP for GTP, and subsequent GTPase activation, while RHO GAPs convert a GTPase into an “efficient” GTPase, increasing GTP hydrolysis and promoting its deactivation. The third subfamily of RHO GDIs can play a dual role: on one side they prevent GTPases activation by RHO GEFs, but, on the other side, they avoid their degradation in the proteasomal. RHO GTPases and their activators, the RHO GEFs, have been historically associated with pro-tumorigenic functions in cancer. In this sense, a widely accepted archetype in the field sustains that RHO GTPases and GEFs alterations in cancer will end up in the hyperactivation of the pathways that depend on their activity, with positive outcomes for tumor cells fitness. Conversely, since RHO GAPs activity can antagonize this process, they were classically associated with a tumor suppressor activity. However, while this paradigm is still valid in many cases, the outcomes obtained from the latest whole-genome and whole-exome sequencing of thousands of human tumors demonstrate that this functional prototype is not extendable to all cases. Firstly, we discovered that human tumors present both gain- and loss-offunction mutations in elements from this pathway, including the RHO GTPases and GEFs. Secondly, we found out that these mutations were not developed at high frequencies across cancer cells. Thirdly, we realized that the overexpression of GTPases and GEFs, proposed as an alternative mechanism that would explain the spurious activation of this pathway in cancer, it is not as a general process as originally thought. Collectively, all these observations challenge the long-held functional archetypes for RHO proteins in cancer cells. In this work, we have carried out a systematic study on the somatic mutations, transcriptomic alterations and copy number variations that 486 genes ascribed to the RHO GTPases pathway present in more than 10,000 human-derived tumors from 33 different cancer types. To that end, we have applied different bioinformatic algorithms, and we developed a new one, to the analysis of multidimensional molecular data obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Then, we validated some of our results in in vitro and in vivo cancer models of KRAS-mutated lung adenocarcinoma, one of the deathliest cancer types in our days.