ESR Project 8: Define prostate-specific cellular mechanism of TRIB3’s tumour suppressor actions
El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos – Universidad Complutense de Madrid (IdISSC-UCM)
Background: Tribbles proteins (and specifically TRIB3) have been implicated in the regulation of cancer progression in animal models. Likewise, TRIB3 up-regulation has been shown to play an important role in the mechanism of action of several anticancer agents and specifically cannabinoids. These and other observations – briefly described in the preliminary data section – settled the bases for the current PhD project proposal.
Preliminary data: Previous work by the IdISSC-UCM group and their collaborators has showed that genetic inactivation of Trib3 enhances the tumorigenic properties of cancer cells, an effect that relies in the overstimulation of the mTORC2/AKT/FOXO axis. In addition, experiments performed with animal models showed that lesions in the prostate of Pten+/- animals were enhanced by TRIB3 genetic inactivation
Salazar et al Cell Death Differ 2015 (http://dx.doi.org/10.1038/cdd.2014.133)
Expected major outcomes:
- Identification of the tumour suppressor role of Trib3 in prostate cancer
- Stablishing the role of TRIB3 on the regulation of the interplay between immune system, adipose tissue and transformed epithelial tissue.
- Identification of possible novel anticancer treatments based in the modulation of the levels and function of TRIB3 in prostate cancer
Details of Year 1 experimental plans:
– Generate prostate cancer cell lines in which Trib3 has been genetically inhibited (knock-down and if considered appropriate CRISPR/Cas9 technology) and overexpressed.
– Analyse the effect of Trib3 silencing and/overexpression on the tumorigenic capacity of prostate cancer cell lines in vitro and in vivo
– Characterise in vitro the responses (e.g. lipid synthesis, migration) of TRIB3-deficient prostate cancer cell lines to inflammatory cytokines.
– Generate prostate selective double Trib3 and Pten KO mice and start the analysis of their phenotype
Supervisors: Guillermo Velasco and Mar Lorente