ESR Project 7: Remote and local control of tumour microenvironment & metabolism through adipocyte Trib-expression’
Tribbles pseudokinases are proteins which were first identified in the firefly Drosophila melanogaster. Tribbles are involved in multiple cellular processes such as regulation of cell cycle, differentiation, metabolism, proliferation, and cellular stress. Tribbles are highly conserved among mammals. The mammalian tribbles family comprises of three proteins encoded by the genes, Trib1, Trib2 and Trib3. In physiological condition, Trib1/3 are involved in adipocyte differentiation. In addition, various studies have shown that tribbles are also involved in the development of several types of cancer including prostate, acute myeloid leukaemia, brain and breast cancer. Prostate cancer (PCa) incidence has significantly increased and it is now the third most commonly diagnosed type of cancer in Europe. Prostate is a walnut sized gland located between the bladder and penis. Prostate gland surrounds the urethra and it functions in empting the urine from the bladder and secreting prostate fluid. Prostate gland is surrounded by periprostatic adipose tissue (PPAT) which functions as an endocrine organ.
PCa is characterized by an excessive proliferation of prostate gland cells. Several lines of evidence suggest that PCa aggressiveness is influenced by the close proximity with PPAT since the adipose cells provide a favourable microenvironment for tumour growth. Indeed, factors secreted by the adipose tissue promote PCa cell migration. A recent study has found that expression of Trib1 was significantly higher in PCa tissues from patients compared to the adjacent normal tissues. Finally, different studies have shown that Trib3 can interact and modulate the activity of oncogenes members of both PI3K-AKT and MAPK/ERK signalling cascades; these are among the best characterized tumorigenic pathways involved in cell proliferation and survival.
Our hypothesis is that tribbles (especially Trib1/3) expressed in adipocytes may contribute to PCa development and aggressiveness. Therefore, this study aims to investigate how defective Trib1 and Trib3 function specifically in adipocytes influences PCa progression. For this purpose, mice with a conditional deletion of Trib1 or Trib3 in adipocytes will be generated and studies will be carried out to assess the effect of these Trib1/3-deficient adipocytes on PCa cells in vitro. Furthermore, the effect of adipocytes with a deletion of Trib1/3 on PCa will be assessed using mouse models in vivo. Overall, this study would give insights into the mechanisms leading to PCa progression specifically taking into account the interaction with the tumour microenvironment.