The main goal of our laboratory is the characterization of the molecular mechanisms of action and regulation of growth factors and growth factor receptors in genitourinary cancer progression.
Dr. Morrione’s current research projects are:
1) Characterization of progranulin action in bladder cancer progression. The growth factor progranulin plays an important role in cell proliferation, wound healing and transformation in several cancer systems. In addition, progranulin regulates inflammation and neurodegeneration, as in fact progranulin has been identified as a causative gene for frontotemporal dementia.
Our laboratory has established a critical role of progranulin in bladder cancer. Progranulin promotes urothelial cancer cell motility and contributes as an autocrine growth factor to the transforming phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin is upregulated in invasive bladder cancer tissues compared to normal bladder controls. These results suggest that progranulin may be critical in promoting the invasive phenotype in urothelial cancer and serve as a novel biomarker for bladder cancer progression. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. Using pull-down assays with recombinant progranulin we have recently identified drebrin, an F-actin binding protein, as a progranulin binding partner in urothelial cancer cells. We are currently characterizing drebrin function in various urothelial cancer cell lines to fully establish its role in progranulin-dependent signaling leading to motility, invasion and anchorage-independent growth. In addition, in vivo experiments are currently under way to establish drebrin action in tumor formation and progression using human tumor xenografts and orthotopic bladder cancer models and a mouse model of lung metastases. We will utilize bladder cancer cells with a specific tropism for pulmonary metastasis (in collaboration with Dr. Renato Iozzo in the Department of Pathology here at Jefferson).
We have also preliminary evidences that drebrin expression is upregulated in bladder cancer tissues compared to normal controls as assessed by IHC on a bladder tissue Microarray.
Collectively, our data suggest that drebrin may exert a relevant functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer progression.
2) Characterization of IGF-IR and IR-A cross-talk with DDR1 and it relevance in bladder cancer progression. Recent work from our laboratory supports the hypothesis that the IGF-IR plays a critical role in bladder cancer by promoting the transition to the invasive phenotype. IGF-IR expression increases with tumor grade in bladder cancer tissues and stimulates the ability of urothelial cancer cells to migrate through and evade a 3D extracellular matrix. We have also demonstrated that the Proline-rich tyrosine kinase 2 (Pyk2) is activated by the IGF-IR, is up-regulated in bladder cancer tissues and it is required for the regulation of IGF-I-induced motility. However, the molecular mechanisms regulating IGF-IR-dependent motility of bladder cancer cells are not yet defined, as is the role of the IGF-IR in bladder cancer progression and metastases. In addition, we do not know whether the IR, and in particular the insulin receptor isoform A (IR-A) together with the IGF-IR, would contribute to the transformation of urothelial cells.
Discoidin domain receptors (DDRs) are RTKs that bind to and are activated by various forms of collagen Unlike other RTKs, DDRs have slow activation kinetics, and Tyr-phosphorylation requires hr after collagen binding. Despite the similar role of the IGF-I system and DDRs in growth regulation, cell adhesion and migration, the potential cross-talk between DDR1 and IGF-IR has not been previously explored but recent data have identified DDR1 as a substrate for the IR-A. We have recently discovered that:  DDR1 was selectively expressed by invasive and metastatic but not by non-invasive urothelial cells, suggesting that this receptor might be directly involved in driving bladder cancer cell invasion,  DDR1 was Tyr-phosphorylated upon stimulation with IGF-I, IGF-II and insulin and was absolutely necessary for IGF-I-induced cell migration, linking these RTKs to bladder cancer progression, and  DDR1 physically interacted with the IGF-IR, IR-A, as well as with Pyk2 and non-muscle myosin IIA heavy chain in a ligand-dependent fashion. These novel findings indicate that DDR1 may regulate IGF-IR and IR-A-dependent bladder cancer cell motility by linking the IGF-IR and IR-A to actomyosin cytoskeleton dynamics.
We are currently performing in vivo experiments to determine DDR1 action in vivo and establish its relevance with the IGF-IR and IR-A in bladder cancer progression. We are additionally examining DDR1 levels in bladder cancer tissues initially using bladder cancer tissue microarrays.
These experiments will not only provide important information required to better understand the molecular mechanisms that regulate tumor formation and progression in bladder cancer at the cellular/biochemical level, but it will also yield valuable information for translational research. Once characterized the role of the IGF-IR, IR and DDR1 in bladder cancer, these studies could contribute to the identification of novel targets for therapeutic intervention in bladder tumors. Furthermore, the IGFI-R, the IR and DDR1 may prove useful clinical biomarkers for the diagnosis and prognosis of bladder cancer.
In collaboration with Dr. Iozzo in the Department of Pathology here at Jefferson we are also investigating the effect of tumor microenvironment and matrix proteins, like decorin, in regulating IGF-IR and IR-A action in bladder cancer progression.
3) Determine sortilin action in the regulation of prostate cancer progression. Sortilin, a single-pass Type I transmembrane protein of the Vps10 family that is localized to the cell surface, secretory, and endocytic compartments of eukaryotic cells. Recently, sortilin has been identified as a novel progranulin binding protein in neuronal cells. However, sortilin acts as negative regulator of progranulin levels and signaling by promoting progranulin endocytosis and its targeting for lysosomal degradation.
Whether sortilin may play a role in bladder or prostate cancer has not bee established. We have recently determined that sortilin is expressed in bladder and prostate cancer cell lines. Significantly sortilin levels are considerably reduced in castration-resistant prostate cancer cells, which express progranulin at high levels.
These results suggest the hypothesis that sortilin may play a role in prostate cancer progression by regulating progranulin levels. Experimental approaches using sortilin overexpression and depletion are currently under way but preliminary experiments suggest that modulating sortilin levels regulates proliferation, motility and anchorage-independent growth of castration-resistant prostate cancer cells.
Future experiments will address sortilin action in vivo using tumor xenograft, orthotopic and metastasis (bone) models and its possible role as a diagnostic or prognostic factor in prostate cancer progression.
Dr. Knudsen’s research endeavors focus on the mechanisms by which androgen governs prostate cancer growth, pathways that deregulate this process in disease progression, and the influence of both environmental and genetic factors on therapeutic response. Dr. Knudsen currently heads the Thomas Jefferson University/Kimmel Cancer Center Prostate Cancer Working Group, striving to facilitate communication and collaborative research among the many talented basic, translational, and clinical researchers at TJU. This Group is also dedicated to increase awareness about the breadth of prostate cancer research at the institution. She is collaborating with Drs. Morrione, Trabulsi, and Gomella on a variety of translational research initiatives.
For more information on Dr. Knudsen, click here.
Dr. Nevalainen's research program focuses on identifying protein kinase signaling pathways that mediate castration-resistant and metastatic growth of prostate cancer cells, with special focus on Stat transcription factors. Recent work from Dr. Nevalainen's laboratory has validated transcription factor Stat5 as a molecular target for therapy development for prostate cancer. Moreover, recent results show that activation of Stat5 in primary prostate cancer predicts early disease recurrence. The current focus of Dr. Nevalainen's research program is on identification of the molecular mechanisms on how Stat5 contributes to castration-resistant growth of prostate cancer and determining the individual roles of Stat5a vs.Stat5b in metastatic dissemination of prostate cancer.
For more information on Dr. Nevalainen, click here.