ESR Project 6: Contribution of prostate-specific TRIB1 expression to prostate cancer pathogenesis, metabolism and remodeling of the microenvironment
Prostate cancer (PC) is the most common cancer among men in Europe and the second worldwide. First and second line therapies (surgery and androgen ablation, respectively) are used for PC patients. However, a fraction of patients fail to respond to these treatments and succumb to the disease, hence raising the need for novel therapies (Chen Y ,.et al 2008). TRIB1, a member of the Tribbles family of serine/threonine kinase-like proteins (pseudokinases), is shown to play a role in prostate cancer survival and cell growth (Tetsuo Mashima ,.et al ,2014).
In this sense, my project has the aim to reveal a better understanding of the role of TRIB1 in prostate cancer. To fulfill this aim, I am going to perform three major approaches: 1.Computational analysis: I will focus on the correlation analysis of TRIB1 vs transcriptome in four human prostate cancer datasets and narrow it to 3 datasets for further analysis such as functional evaluation of correlated genes. This will allow us to identify potential pathways of interest related to TRIB1. 2. Functional analysis: I will ectopically express inducible TRIB1 using TRIPZ vector and also perform inducible silencing of TRIB1 using TET-LKO vector in PC cell lines in order to evaluate the biological consequences of TRIB1 manipulation in vitro and in vivo (Xenografts). In order to mechanistically study the function of TRIB1, I will take advantage of the bioinformatics analysis (approach 1) and perform also OMICS-based candidate search (transcriptomics, proteomics upon TRIB1 manipulation). 3. Causal contribution of TRIB1 to PC: in this last approach, I will employ different mouse models such as: 1. Mice with conditional deletion of TRIB1 alone or together with PTEN loss 2. Mice with transgenic expression of TRIB1 in prostrate tissue, alone or together with PTEN heterozygous and homozygous loss. Taken together, I believe that this project will allow me to identify the potential contribution of TRIB1 to tumor formation, progression and/or metastasis, to reveal its cooperative partners as well as to introduce novel therapeutic strategies in PC.