Bladder cancer is one of the most common cancer in the United States with 70,530 estimated cases and 14,680 estimated deaths in 2010. Regardless of the treatment modality, bladder cancer often recurs and metastasizes with very poor prognosis. Understanding the cellular and molecular mechanisms that regulate the biology of bladder cancer progression and invasion would be critical to develop new forms of treatments against this devastating disease. We have established that the growth factor progranulin plays a critical role in bladder cancer by regulating motility and invasion of malignant urothelial cells and demonstrated that progranulin acts as an autocrine growth factor. Moreover we have shown an increased expression of progranulin in invasive bladder tumors vis-?-vis normal bladder. Collectively, our results support the hypothesis that progranulin may play a critical role as an autocrine growth factor in the establishment and progression of bladder cancer. Despite the strong connections with growth control and cancer, progranulin's mode of action is still poorly characterized. We have discovered that the focal adhesion kinase Pyk2 is activated by progranulin and its expression is increased in bladder cancer tissues. Conversely, knockdown of progranulin inhibits motility and anchorage-independent growth of metastatic bladder cancer cells. This indicates that progranulin may play a key role in the invasive (high motility) phenotype. Using pull-down experiments and proteomics we have identified for the first time drebrin as a membrane protein interacting with progranulin. Drebrin is an actin- binding protein involved in cell adhesion, motility and calcium signaling. Thus, we hypothesize that drebrin might be part of a supramolecular complex involved in progranulin signaling. We will test our hypothesis and accomplish the objectives of this application through the following specific aims: [1] Determine the mechanisms of progranulin action in bladder cancer cells. [2] Investigate the function of drebrin, a novel progranulin interacting protein, in the regulation of motility and invasion of bladder cancer cells. [3] Characterize the in vivo roles of progranulin, Pyk2 and drebrin in bladder cancer formation and progression. The expected results will provide not only novel information toward a better understanding of the mechanisms that regulate tumor cell motility but will also provide invaluable insight into the role of the progranulin signaling pathway in regulating the transition to the invasive phenotype in urothelial neoplasia. Once characterized the role of the progranulin pathway in bladder cancer formation and progression, these studies will greatly contribute to the identification of novel targets for therapeutic intervention in bladder tumors. In addition, progranulin, Pyk2 and drebrin may prove as novel diagnostic and/or prognostic biomarkers for bladder tumors.

Public Health Relevance

Bladder cancer is the one most common cancer in the United States with a raising 70,530 estimated cases and 14,680 estimated deaths in 2010, but very little is still known about the molecular mechanisms that determine tumor formation in the bladder urothelium. We have discovered that progranulin, Pyk2 and drebrin play an essential role in bladder cancer by promoting motility and invasion of bladder cancer cells, which suggest that progranulin may promote the transition to the invasive stage of bladder cancer. This proposal will not only provide important information required to better understand the mechanisms that regulate tumor formation in bladder cancer, but it will yield valuable information for translational research;once characterized progranulin and progranulin signaling proteins in bladder cancer formation/progression, these studies will greatly contribute to the identification of novel targets for therapeutic intervention in bladder tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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Thomas Jefferson University
Schools of Medicine
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Gubbiotti, Maria A; Seifert, Erin; Rodeck, Ulrich et al. (2018) Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin. J Biol Chem 293:16940-16950
Schaefer, Liliana; Tredup, Claudia; Gubbiotti, Maria A et al. (2017) Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology. FEBS J 284:10-26
Torres, Annabel; Gubbiotti, Maria A; Iozzo, Renato V (2017) Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis. J Biol Chem 292:5055-5069
Vella, Veronica; Malaguarnera, Roberta; Nicolosi, Maria Luisa et al. (2017) Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells. Oncotarget 8:43248-43270
Gubbiotti, Maria A; Neill, Thomas; Iozzo, Renato V (2017) A current view of perlecan in physiology and pathology: A mosaic of functions. Matrix Biol 57-58:285-298
Neill, Thomas; Sharpe, Catherine; Owens, Rick T et al. (2017) Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy. J Biol Chem 292:16211-16220
Pozzi, Ambra; Yurchenco, Peter D; Iozzo, Renato V (2017) The nature and biology of basement membranes. Matrix Biol 57-58:1-11
Belfiore, Antonino; Malaguarnera, Roberta; Vella, Veronica et al. (2017) Insulin Receptor Isoforms in Physiology and Disease: An Updated View. Endocr Rev 38:379-431
Neill, Thomas; Schaefer, Liliana; Iozzo, Renato V (2016) Decorin as a multivalent therapeutic agent against cancer. Adv Drug Deliv Rev 97:174-85
Matà, Roberta; Palladino, Chiara; Nicolosi, Maria Luisa et al. (2016) IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget 7:7683-700

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