Kenneth L. van Golen, Ph.D.

Teaching

• BISC612-Advanced Cell Biology
• BISC 850 - Advanced Topics in Biology: The Rho GTPases

Research Interests

The main interest of my laboratory is to understand the biology of Inflammatory breast cancer (IBC).  IBC is an extremely aggressive form of breast cancer that is phenotypically unique form of breast cancer.  IBC is hallmarked by distinct changes in the skin changes that resemble an infection or mastitis.  IBC affects younger women (typically in thier late 20's or early 30's) and progresses rapidly.  The rapid progression of the disease is thought to occur because of the propensity of the tumor cells to invade and reside in the dermal lymphatic vessels of the skin overlying the breast. 

In 1999 our laboratory found that RhoC GTPase, one member of the Rho family, was overexpressed in inflammatory breast cancer.   Later, we found that RhoC over expression was a prognostic marker for metastasis in small breast tumors (<1 cm in size). Since then we have begun to look at how RhoC confers a metastatic phenotype to inflammatory breast cancer and how it interacts with other Rho GTPases. Our studies have expanded to include pancreatic cancer and prostate cancer bone metastasis.

The Rho GTPases comprise a group of 23 small GTP binding proteins that play a significant role in nearly every cellular process. One of the most characterized roles of the Rho proteins is their ability to reorganize the cell cytoskeleton. Signals from the extracellular environment, transduced through growth factor receptors and/or cell adhesion molecules leads to the coordinated activation of Rho proteins and reorganization of the cytoskeleton. In turn, this leads to changes in cells shape, polarity, migratory and invasiveness.

The potent ability of the Rho proteins to affect cell migration and invasion has many implications for the dissemination and spread of cancer and in normal processes such as development and immunity. RhoC GTPase is associated with metastatic spread and thus appears to be a metastatic switch.   Interestingly, RhoC is 91% homologous on the protein level to RhoA GTPase, yet the two proteins have completely different functions in the cell.  One of our goals is to understand what makes these two GTPases distinct from one another.

A complete understanding of how the Rho proteins, particularly RhoC, can influence progression of a cancer cell to become metastatic is key to the development of anti-metastatic therapies.  Aside from IBC our laboratory also has interests in understanding the mechansims underlying prostate cancer skeletal metastasis. 

Current Projects

• Understanding the molecular mechanisms of inflammatory breast cancer metastasis - The goal of this project is to understand how inflammatory breast cancer metastasizes.  We have developed an in vitro model of IBC emboli formation that accurately resembles IBC emboli in the patient.  Using this model we are beginning to unravel the molecules and signaling pathways involved in IBC metastasis.  In particular we are studying the role of RhoC with Akt/Protein Kinase B and with the scaffolding molecule caveolin-1.  We are also studying the role of platelet derived growth factor alpha in conferring a survival advantage to IBC cells.
• The role of Rho GTPases in prostate cancer bone metastasis - The goal of this project is to understand the contribution of individual Rho GTPases during the process of binding to bone marrow endothelial cells, tumor cell diapedesis (transendothelial cell migration) and invasion through the bone stroma.
• Determining the differences between RhoA and RhoC GTPases-  Since RhoA and RhoC share 91% homology we are using an advanced genetic and imaging approach to understand the differences in the spatial and temporal activation of the proteins. 

Selected Publications

• Chatterjee M and van Golen KL.  Breast cancer stem cells survive periods of farnesyl-transferase inhibitor-induced dormancy by undergoing autophagy. Bone Marrow Res. 2011;2011:362938. Epub 2011 Jul 7.PMID:22046561
• Chatterjee M, Sequeira L, Jenkins-Kabaila M, Dubyk CW, Pathak S, van Golen KL. Individual rac GTPases mediate aspects of prostate cancer cell and bone marrow endothelial cell interactions. J Signal Transduct. 2011;2011:541851. Epub 2011 Jun 27 PMID:21776386
• Chatterjee M and van Golen KL. Farnesyl transferase inhibitor treatment of breast cancer cells leads to altered RhoA and RhoC GTPase activity and induces a dormant phenotype.  Int J Cancer. 2011 Jul 1;129(1):61-9. doi: 10.1002/ijc.25655. Epub 2010 Oct 26.  PMID:  20824700
• Vermeulen PB, van Golen KL and Dirix LY. Angiogenesis, lymphangiogenesis, growth pattern, and tumor emboli in inflammatory breast cancer: a review of the current knowledge.  Cancer. 2010 Jun 1;116(11 Suppl):2748-54
• Cooper CR, Graves B, Pruitt F, et al. Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha. J Cell Biochem. 2008;104(6):2298–2309.
• Hall CL, Dubyk CW, Riesenberger TA, Shein D, Keller ET, van Golen KL. Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase. Neoplasia. 2008;10(8):797–803.
• Miles FL, Pruitt FL, van Golen KL, Cooper CR. Stepping out of the flow: capillary extravasation in cancer metastasis. Clin Exp Metastasis. 2008;25(4):305–324.
• Sequeira L, Dubyk CW, Riesenberger TA, Cooper CR, van Golen KL. Rho GTPases in PC-3 prostate cancer cell morphology, invasion and tumor cell diapedesis. Clin Exp Metastasis. 2008;25(5):569–579.
• van Golen KL, Ying C, Sequeira L, et al. CCL2 induces prostate cancer transendothelial cell migration via activation of the small GTPase Rac. J Cell Biochem. 2008;104(5):1587–1597.
• Hall CL, Dai JL, van Golen KL, Keller ET, Long MW. Type I collagen receptor (alpha 2 beta 1) signaling promotes the growth of human prostate cancer cells within the bone. Cancer Res. 2006;66(17):8648–8654.
• Van den Eynden GG, Van Laere SJ, Van der Auwera I, et al. Overexpression of caveolin-1 and -2 in cell lines and in human samples of inflammatory breast cancer. Breast Cancer Res Treat. 2006;95(3):219–228.
• van Golen CM, Schwab TS, Kim B, et al. Insulin-like growth factor-I receptor expression regulates neuroblastoma metastasis to bone. Cancer Res. 2006;66(13):6570–6578.
• van Golen KL. Is caveolin-1 a viable therapeutic target to reduce cancer metastasis? Expert Opin Ther Targets. 2006;10(5):709–721.
• Van Laere SJ, Van den Eynden GG, Van der Auwera I, et al. Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling. Breast Cancer Res Treat. 2006;95(3):243–255.
• Yao H, Dashner EJ, van Golen CM, van Golen KL. RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility. Oncogene. 2006;25(16):2285–2296.
• Zhang L, Chenwei L, Mahmood R, et al. Identification of a putative tumor suppressor gene Rap1GAP in pancreatic cancer. Cancer Res. 2006;66(2):898–906.
• Kleer CG, Griffith KA, Sabel MS, et al. RhoC-GTPase is a novel tissue biomarker associated with biologically aggressive carcinomas of the breast. Breast Cancer Res Treat. 2005;93(2):101–110.
• Lin M, DiVito MM, Merajver SD, Boyanapalli M, van Golen KL. Regulation of pancreatic cancer cell migration and invasion by RhoC GTPase and caveolin-1. Mol Cancer. 2005;4(1):21.
• Radunsky GS, van Golen KL. The current understanding of the molecular determinants of inflammatory breast cancer metastasis. Clin Exp Metastasis. 2005;22(8):615–620.
• van Golen KL, Bao LW, DiVito MM, Wu ZF, Prendergast GC, Merajver SD. Reversion of RhoC GTPase-induced inflammatory breast cancer phenotype by treatment with a farnesyl transferase inhibitor. Mol Cancer Ther. 2002;1(8):575–583.
• van Golen KL, Wu ZF, Qiao XT, Bao LW, Merajver SD. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res. 2000;60(20):5832–5838.
• van Golen KL, Davies S, Wu ZF, et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin Cancer Res. 1999;5(9):2511–2519.
• van Golen KL, Wu ZF, Bao LW, Merajver SD. RhoC GTPase induces a motile and invasive phenotype in inflammatory breast cancer. Clin Exp Metastasis. 1999;17(9):745.