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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

Related references:

Salazar et al Cell Death Differ 2015 (http://dx.doi.org/10.1038/cdd.2014.133)

Expected major outcomes:

  1. Identification of the tumour suppressor role of Trib3 in prostate cancer
  1. Stablishing the role of TRIB3 on the regulation of the interplay between immune system, adipose tissue and transformed epithelial tissue.
  1. 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