Molecular Mechanisms of Cancer Signal Transduction Program

Our research group is focused on the characterization of the molecular mechanism of action and regulation of cancer cell signaling with particular emphasis on progranulin function in solid tumors, including bladder and mesothelioma. We demonstrated that the growth factor progranulin plays a critical role in bladder cancer by modulating tumor cell motility and invasion. Progranulin regulates actin remodeling by interacting with drebrin, an actin binding protein that regulates tumor growth. We also discovered that progranulin depletion inhibits epithelial-to-mesenchymal transition and reduces in vivo tumor growth. Moreover, progranulin depletion sensitizes urothelial cancer cells to cisplatin treatment. Until recently, the progranulin signaling receptor remained unidentified, precluding a full understanding of progranulin action in tumor cell biology. We recently identified EphA2, a member of a large family of receptor tyrosine-kinases, as the functional receptor for progranulin. Progranulin evoked Akt- and Erk1/2-mediated EphA2 phosphorylation at Ser897, which could drive bladder tumorigenesis. In addition, EphA2 depletion severely blunted progranulin-dependent motility and anchorage-independent growth, and sensitized bladder cancer cells to cisplatin treatment. The discovery of EphA2 as the functional signaling receptor for progranulin and the identification of novel downstream effectors offer a new avenue for understanding the underlying mechanism of progranulin action and may constitute novel clinical and therapeutic targets not only in bladder cancer but also in mesothelioma, where we have evidence supporting a critical role for the progranulin/EphA2 oncogenic axis in this rare and aggressive neoplasia. Additional projects are aimed at the functional characterization of the tumor suppressor p107 and the mechanisms regulating its stability.