Title: TROP2, a stem cell marker with oncogenic potential in prostate cancer
Funder: Tenovus Cancer Care

Abstract: Prostate cancer (PCa) is a leading cause of death among males in the developed world, due to hormone independent incurable disease with widespread metastasis to bone and other organs. Recently, prostate tumour initiating stem-like cells were isolated in man (1) and mouse (2). These cells likely survive androgen ablation therapy, due to lack of androgen receptor expression and represent cells capable of reinitiating tumours. TROP2 is a cell surface marker that identifies a subpopulation of prostate basal cells with stem cell characteristics (3). We present important novel evidence that TROP2 is a marker for human prostate tumour initiating stem-like cells. Cell lysates have high levels of TROP2 expression and high levels of soluble TROP2 extracellular domain (TROP2-ECD) in medium. We have identified for the first time that TROP2 is cleaved by disintegrin and metalloproteinases (ADAMs) leading to the loss of the TROP2-ECD from the cell surface. Further processing occurs through γ-secretase dependent cleavage, which leads to perinuclear localisation of the cleaved TROP2-intracellular domain (TROP2-ICD). Our preliminary results support the hypothesis that TROP2 processing by ADAMs and γ-secretase regulates TROP2 signalling in PCa, similar to the TROP2 homologue EpCAM (4) (Fig.1). High TROP2 expression levels induce proliferation, cell cycle progression, migration and anchorage independent growth; predict metastasis and poor outcome in ovarian, colorectal, gastric, pancreatic and oral cancer (3;5-11). However, the role of TROP2 in PCa has not been investigated and the biological function and signalling potential of TROP2 in cancer remains unclear. We are in a strong position to investigate the role and molecular mechanisms of TROP2 dependent signalling in PCa and test the targeting strategies outlined in red (Fig. 1). This investigation is timely and will explore points of therapeutic intervention in order to reverse the “oncogenic” phenotype in cells displaying high TROP2 expression as well as uncovering the contribution of TROP2 cleavage products to “oncogenic” signalling by TROP2 in PCa. Our hypothesis will allow us to explore numerous points for therapeutic intervention for PCa treatment, as well as to investigate whether TROP2-ECD is a diagnostic marker in PCa. We will investigate whether inhibition of TROP2 expression using shRNA approaches or inhibition of proteolytic processing by ADAMs or γ-secretase can reverse the above cellular phenotypes attributed to high TROP2 expression. These phenotypes are linked to oncogenic cellular transformation and are involved in promoting invasion and metastasis and thus the discovery of inhibitory pathways represent novel avenues of therapeutic intervention. We will also test whether antibodies recognising different domains in TROP2 can block proliferation, migration and anchorage dependent growth of PCa cells could impact diagnosis and therapy options in PCa as it informs the physician on treatment options.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS