Tien Hsu, Ph.D.
|PI Name: Tien Hsu, Ph.D.
Title: Professor of Medicine
Research Interests: Epithelial Morphogenesis; epithelial tumor formation.
Epithelia are the cell layers that line the organs and form the tubular systems, and are the origin of 80% of all solid tumors. We are interested in how epithelial tissues are established during development and how they turn tumorigenic. We employ a cross-species experimental strategy by comparing the genetic system Drosophila, mouse models and human cell cultures. There are several specific areas of interest:
1) Establishing and maintaining the epithelial tissues involve complicated cellular mechanisms and interactions between cells and their environment. The follicular epithelium that envelopes the Drosophila egg is an excellent model for studying developmental regulation of epithelial morphogenesis and for analyzing the epithelial-to-mesenchymal transition that underlies the initiation of tumor metastasis. We are focusing on the function of two human tumor suppressor gene homologs in this model system: VHL and Nm23. We are analyzing a novel vesicle transport function of these two genes as well as their roles in regulating microtubule organization. We found that regulated protein transport and localization is critical for maintaining the epithelial cell integrity. Such mechanisms should be regarded as an important level of cellular regulation of gene expression.
|Confocal laser scanning images of Drosophila egg chambers of wild-type (top panel) and VHL mutant, stained for aPKC (green), beta-catenin (red), and nuclei (blue). The wild-type egg shows organized single-layer epithelial follicle cells with aPKC at the apical cortex and beta-catenin at the apical-lateral corners of the cell junctions. In VHL mutant, both aPKC and beta-catenin become diffused and the follicle cells become invasive (arrows) into the underlying germ cell complex.|
(2) We are also interested in a second type of epithelial tissues – those comprise the tubular systems. Tubular systems are the functional architecture of many organs, including kidney, lung and mammary glands. The functions of VHL and Nm23 are studied in the Drosophila tracheal tubule system and in human renal carcinoma and primary kidney tubule cells. We identified an interesting intra-cellular vesicle transport system that differentially regulates the cell surface localization of different growth factor receptors. Disrupted balance of subcellular localization of these receptors in the VHL mutant, probably acting through the loss of function of nm23, results in abnormal cell invasion and migration. These findings provided an excellent model for studying the control of cell migration in development and in tumor metastasis.
|Nm23 is a potential human metastasis inhibitor but its exact cellular function is unclear. Here we show that the mutations in the Drosophila homolog result in ectopic filopodia formation in the migrating tracheal cells (arrows in bottom panels) as compared to the wild-type cell, which usually sprout one or two filopodia (upper pane).|
(3) VHL is a tumor suppressor gene the mutations of which are the genetic cause of the familial von Hippel-Lindau disease. The disease is characterized by several prominent neoplasia including kidney cancer, hemangioblastoma (over-growth of blood vessels) in the central nervous system, among others. Current studies identified VHL as a key regulator of several important oncogenic pathways. These studies, however, cannot explain the organ specificity of the VHL lesions. Using developmental and mouse knockout models, we aim to unravel the reason of this intriguing tissue specificity. We have identified a possible signaling pathway that is uniquely oncogenic in the kidney environment when VHL is mutated.
|A renal carcinoma cell stained for FGF receptor 1 (red) and the von Hippel-Lindau tumor suppressor protein (green). The two proteins co-reside in the early endosomes upon FGF2 stimulation (inset).|
(4) VHL tumor suppressor gene mutation is responsible for >70% of the renal cell carcinoma of the clear-cell type. We have developed a conditional Vhl knockout mouse model, which exhibits inflammation and fibrosis in the kidney pre-cancerous lesions. This implicates the importance of inflammation and fibrotic stroma in tumor progression. The ongoing work aims to characterize the cellular events in the mutant epithelial cells and in the precancerous stroma during early events in tumorigenesis.
Mouse kidney sections from (A) wild-type and (B) Vhl kidney tubule conditional knockout. Mutant kidney shows minicysts (dilated tubules), infiltrating immune cells (red arrowheads) and clear cells (arrow).
Tien Hsu, PhD
Professor of Medicine
Boston University School of Medicine
Section of Hematology/Oncology
650 Albany St., EBRC 440
Boston, MA 02118
Email: Tien Hsu, Ph.D.
Richard Near, PhD – Research Assistant Professor
Hannah Bader, PhD - Post-Doctoral Fellow
Tracy Pritchett, PhD - Post-Doctoral Fellow
Hsiao-Rong Chen – Graduate Student
(#: Student; †: postdoc)
Adereth, Y.#, Dammai, V., Kose, N., Li, R. and Hsu, T. (2005) RNA-dependent integrin 3 protein localisation regulated by the Muscleblind-like protein MLP1, Nature Cell Biology 7: 1240-1247 [Accompanied by News and Views Nature Cell Biology 7: 1155-1156] [Highlighted in Nature Cell Migration Gateway, Dec. 2005] [Abstract] [Full text]
Arquier, N., Vigne, P., Duplan, E., Hsu, T., Therond, P.P., Frelin, C. and D’Angelo, G. (2006) Analysis of the hypoxia-sensing pathway in Drosophila melanogaster. Biochem. J., 393: 471-480. [Abstract] [Full text]
Hsu, T. (co-corresponding author), Adereth, Y.†, Kose, N. and Dammai, V. (2006) Endocytic function of Von Hippel-Lindau tumor suppressor protein regulates surface localization of FGF receptor 1 and cell motility. J. Biol. Chem. 281: 12069-12080. [Editor's Choice, Cancer, Science's STKE, May 2006] [Abstract] [Full text]
Hsouna, A.†, Lawal, H.O., Izevbaye, I. and Hsu, T. (co-corresponding author) and O’Donnell, J.M. (2007) Drosophila dopamine synthesis pathway genes regulate tracheal morphogenesis. Dev. Biol. 308: 30-43. [Abstract] [Full text]
Nallamothu, G.†, Woolworth, J.A.#, Dammai, V. and Hsu, T. (2008) awd, the homolog of metastasis suppressor gene Nm23, regulates Drosophila epithelial cell invasion. Mol. Cell. Biol. 28: 1964–1973. [Abstract] [Full text]
Chintalapudi, M. R.†, Markiewicz, M., Kose, N, Dammai, V., Championl, K.J.#, Hoda, R. S., Trojanowska, M. and Hsu, T. (2008) Cyr61/CCN1 and CTGF/CCN2 mediate the pro-angiogenic activity of VHL mutant renal carcinoma cells. Carcinogenesis 29: 696-703. [Abstract] [Full text]
Champion, K.J.#, Guinea, M.†, Dammai, V. and Hsu, T. (2008) Endothelial function of von Hippel-Lindau tumor suppressor gene: control of FGF receptor signaling. Cancer Research 68: 4649-4657. [Abstract] [Full text]
Bu, S., Kapanadze, B., Hsu, T. and Trojanowska, M. (2008) Opposite effects of dihydrosphingosine 1-phosphate and sphingosine 1-phosphate on TGFbeta/Smad pathway are mediated through the PTEN/PPM1A dependent pathway. J. Biol. Chem. 283:19593-19602. [Abstract] [Full text]
Mahajan, S., Dammai, V., Hsu. T. and Kraft, A.S. (2008) Hypoxia-inducible factor-2 regulates the expression of TRAIL receptor DR5 in renal cancer cells. Carcinogenesis 29: 1734-1741. [Abstract] [Full text]
Woolworth, J.A.#, Nallamothu, G.†, and Hsu, T. (2009) The Drosophila metastasis suppressor Nm23 homolog, awd, regulates epithelial integrity during oogenesis. Mol. Cell. Biol. 29: 4679-4690. [Selected for cover photo]. [Abstract] [Full text]
Duchi, S.#, Fagnocchi, L., Cavaliere, V., Hsouna, A.†, Gargiulo, G. and Hsu, T. (2010) Drosophila VHL tumor suppressor gene regulates epithelial morphogenesis by promoting microtubule stability. Development 137:1493-1503. [Featured "In This Issue"]. [Abstract] [Full Text]
Hsouna, A.†, Kose, N., Guinea, M.†, Dammai, V. and Hsu, T. (2010) Drosophila von Hippel-Lindau tumor suppressor gene regulates epithelial tubule migration and lumen formation by promoting endocytosis. Mol. Cell. Biol. 30:3779-3794. [Featured in "Spotlight"][Selected for cover photo]. [Abstract] [Full Text]