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Lung Biology Center
Faculty Bios
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V. Courtney Broaddus, M.D.
Professor of Medicine
University of California San Francisco
UCSF Box 0854
tel: 415-206-3513
fax: 415-206-4123
additional websites:
Pulmonary & Critical Care Division

Dr. Broaddus came to UCSF from the East coast, where she received her undergraduate degree from Duke University and her MD from Univ. of Pennsylvania. She remained at the Hospital of the University of Pennsylvania for residency. At this point, she ventured west to start her pulmonary fellowship at UCSF. After research training in the Cardiovascular Research Institute with Dr. Norman Staub, Dr. Broaddus joined the faculty at the San Francisco General Hospital, later joining the research group at the Lung Biology Center where she now has her laboratory. Since 1998, she has served as Chief of the Division of Pulmonary and Critical Care Medicine at SFGH.

Dr. Broaddus spent the year 2001-2002 on sabbatical in the laboratory of Dr. Gerard Evan, at the UCSF/Mt. Zion Cancer Center studying basic mechanisms of apoptosis in malignancy. Following the sabbatical, she has continued her work in the mechanisms of apoptosis and apoptotic synergy in tumors. As of January 1, 2004, she will be the Associate Director of the Lung Biology Center.

Research Interests

Apoptosis is a highly regulated process of cell death, allowing the deletion of cells that are damaged or otherwise targeted for destruction. Resistance to apoptosis underlies both the development and the survival of tumors. Understanding the sites of resistance in tumors may lead to more effective therapy. Two signaling pathways are known to activate the proteases called caspases that mediate apoptosis: one, the DNA damage pathway which involves a mitochondrial step in order to activate caspases and the other the death ligand pathway which can bypass mitochondria to activate caspases directly. Crosstalk between the pathways may lead to synergistic apoptotic responses.

We study apoptosis in mesothelioma and lung cancer lines, as models for highly resistant solid tumors. A major focus of the laboratory is 1) to identify mechanisms of resistance to apoptosis in these lines and 2) to identify means of amplifying apoptosis. We have now described a synergistic apoptotic response of mesothelioma lines when exposed to both a death ligand, TNF-related apoptosis inducing ligand (TRAIL), and chemotherapeutic agents. The synergy can be shown to involve amplification of mitochondrial depolarization and amplified release of cytochrome c. We are now studying the signaling steps by which these two pathways (death receptor and DNA damage) converge on the mitochondria and amplify apoptotic death. Other synergistic combinations appear to act at different levels within the cell, e.g. by increasing expression of the death receptors. We have recently found that, in our p53 inactive cells, DNA damage sensitizes to apoptosis via the JNK stress activated pathway. Some examples of interest are the use of TRAIL or fas ligand together with proteasome inhibitors, with NFkappa B inhibition, and with stimulators of JNK signals to bypass DNA damage.

In other work, we are developing 3-dimensional models for studying apoptotic resistance in tumor cell lines and in tumors themselves. Tumor cells grown on non-adherent surfaces clump together and remodel to form multicellular tumor spheroids. These tumor cells grown as spheroids acquire a high level of resistance to treatments that are successful against the same cells when grown as a monolayer. We are interested in the mechanisms of resistance in this more relevant 3-dimensional model. In addition, we are growing actual tumors (mesothelioma and lung cancers) in vitro by mincing the tumors and allowing them to grow on non-adherent surfaces. In this environment, the tumor fragments remodel into spheroids and remain viable and representative of the original tumor for weeks. We are studying this in vitro tumor model for mechanisms of apoptotic resistance in human tumors. When compared to 2-dimensional monolayer cell culture, the 3-dimensional multicellular spheroids and tumor fragment spheroids provide models more relevant to actual tumors. As such, we are applying the mechanisms learned in cell monolayers for their applicability to the more relevant and complex systems.

Selected Publications

Broaddus VC, Yang L, Scavo LM, Ernst JD, Boylan AM. Asbestos induces apoptosis of human and rabbit pleural mesothelial cells via reactive oxygen species. J Clin Invest 1996; 98:2050-2059. (* identified by the Editors as being of broad interest) (abstract)

Broaddus VC, Yang L, Scavo LM, Ernst JD, Boylan AM. Crocidolite asbestos induces apoptosis of pleural mesothelial cells: Role of reactive oxygen species and poly (ADP-ribosyl) polymerase. Environ Health Perspect 1997; 105 (Suppl 5):1147-1152. (abstract)

Broaddus VC. Asbestos, the mesothelial cell and malignancy: a matter of life or death. Am J Respir Cell Mol Biol 1997; 17:657-659.

Narasimhan SR, Yang L, Gerwin BI, Broaddus VC. Resistance of pleural mesothelioma cell lines to apoptosis: relation to expression of Bcl-2 and Bax. Am J Physiol (Lung Cell Mol Physiol) 1998; 275(19): L165-L171. (abstract)

Ernst JD, Yang L, Broaddus VC. Preparation and characterization of an endogenously fluorescent annexin for detection of apoptotic cells. Anal Biochem 1998; 260:18-23. (abstract)/(full text)

Perkins RC, Broaddus VC, Shetty S, Hamilton S, Idell S. Asbestos upregulates expression of the urokinase-type plasminogen activator receptor on mesothelial cells. Am J Respir Cell Mol Biol 1999; 21:637-646. (abstract)

Marchi E, Liu W, Broaddus VC. Mesothelial cell apoptosis is confirmed in vivo by morphologic change in cytokeratin distribution. Am J Physiol (Lung Cell Mol Physiol) 2000; 278: L528-L535. (abstract)

Levresse V, Renier A, Levy F, Broaddus VC, Jaurand M-C. DNA breakage in asbestos-treated normal and transformed (TSV40) rat pleural mesothelial cells. Mutagenesis 2000; 15(3): 239-244. (abstract)

Liu W, Ernst JD, Broaddus VC. Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage and apoptosis in mesothelial cells. Am J Respir Cell Mol Biol 2000; 23(3): 371-378.

Wu J, Liu W, Koenig K, Idell SI, Broaddus VC. Vitronectin adsorption to chrysotile asbestos increases phagocytosis and toxicity for mesothelial cells. Am J Physiol (Lung Cell Mol Physiol) 2000; 279:L916-L923. (abstract)

Liu W, Bodle E, Chen JY, Rosen GD, Broaddus VC. TNF-related apoptosis inducing ligand (TRAIL) and chemotherapy cooperate to induce apoptosis in human mesothelioma cell lines. Am J Respir Cell Mol Biol. 2001;25:111-118. (abstract)/(full text)

Fjellbirkeland L, Cambier S, BROADDUS VC, Hill A, Brunetta P, Dolganov G, Jablons D, Nishimura SL. Integrin avb8-mediated activation of TGF-b inhibits human airway epithelial proliferation in intact bronchial tissue. Am J Pathol 2003; 163(2):533-542. (full text )

Vivo C, Liu WH, BROADDUS VC. C-Jun N-terminal kinase contributes to apoptotic synergy induced by TRAIL plus DNA damage in chemoresistant, p53 inactive mesothelioma cells. J Biol Chem 2003; 278(28):25461-7. (full text )

BROADDUS VC, Vivo C, Finch AF, Hunt A, Evan GE. BID mediates apoptotic synergy between TNF-related apoptosis inducing ligand (TRAIL) and DNA damage. (In preparation)

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