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 is spending 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 http://cc.ucsf.edu/evan/index.html. Currently, she is Associate Director of the Lung Biology Center at SFGH where she directs a lab investigating apoptosis in thoracic malignancy.
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. Some examples of interest are the use of TRAIL or fas ligand together with proteasome inhibitors, and with inhibitors of various survival pathways such as Akt or mTOR. In parallel in vivo studies, we are exploring synergistic effects in a nude mouse model of mesothelioma.
In related work, we are investigating resistance mechanisms in 3-dimensional, clinically relevant models of tumors. To do this, we have developed means of maintaining human mesothelioma and lung cancer tissues in vitro, as tumor fragment spheroids (2-4 mm diameter). These spheroids maintain the tumor cells as proliferative, viable cells for weeks to months, together with the extracellular matrix and the non-malignant cells found in the original tumor. Using the tumor spheroids, we will investigate whether our interventions can induce apoptosis of tumor cells in a more realistic setting than is represented in monolayer culture of cell lines.
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)/(pdf)
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. (abstract)/(pdf)
Mutti L, BROADDUS VC. Malignant mesothelioma as both a challenge and an opportunity. Oncogene 2004; 23:9155-9161. (abstract)/(pdf)
BROADDUS VC, Dansen TB, Abayasiriwardana KS, Finch AF, Swigart LB, Hunt AE, Evan GI. BID mediates apoptotic synergy between TRAIL and DNA damage. J Biol Chem 2005; 280(13):12486-12493. (abstract)/(pdf)
Kim KU, Wilson SM, Abayasiriwardana KS, Collins R, Fjellbirkeland L, Xu Z, Jablons DM, Nishimura SL, BROADDUS VC. A novel in vitro model of human mesothelioma for studying tumor biology and apoptotic resistance. Am J Respir Cell Mol Biol. 2005; 33(6):541-8. (abstract)/(pdf)
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