Bangyan L. Stiles, PhD
Associate ProfessorPharmacology and Pharmaceutical Sciences
- Cancer Cell Biology
- Cancer Genetics
- Cell Cycle
- Growth & Proliferation
- Cell Death
- Signal Transduction
- Stem Cell Biology
- Developmental Biology
- Cancer Biology
- 9121 HSC
- PSC 402
- (323) 442-2184
- (323) 442-7473
BS 1990 Food Chemistry - Jinan University, P.R. China
MS 1994 Nutrition - University of Tennessee, Knoxville, TN
PhD 1998 Nutritional Biochemistry - University of Texas Austin/MD Anderson Cancer Center
Postdoctoral Research Fellowship:
1999 - 2001 Howard Hughes Medical Research Institute, UCLA
2001 - 2003 UCLA School of Medicine
Our laboratory is interested in the role of lipid phosphatase PTEN and its signaling pathway in cancer and diabetes. The primary function of PTEN is to inhibit the PI3K/AKT pathway. Through regulating this pathway, PTEN plays a role in tumor development, tissue regeneration as well as glucose and lipid metabolism. We have developed several animal models that carry deletion of Pten to study tissue regeneration as well as the link between energy metabolism and tumorigenesis.
The Role of Nutrient Regulated Growth in Hepatocarcinogenesis
One project we are focusing on in the lab is the role of energy sensing in cell growth/survival regulation. We have shown that deletion of PTEN in the liver led to a fatty liver and increased insulin sensitivity phenotype at an early age. As the animals aged, they eventually developed hepatocarcinoma. The two phased development of heptatocarcinoma in this model closely mimics the human HCC progression. Using this model, we are probing two questions in liver cancer:
How liver cancer progress from fatty liver? To answer this question, we are focusing on the interaction between Pten regulated mitogenic PI3K signaling and an energy sensing LKB/AMPK signaling pathway. The Pten deletion model provided us with a unique tool to study the role of energy balance and tumor development. Cellular energy status is regulated by a fuel gauge sensor protein AMPK. When cellular energy levels are low, AMPK signals compete with cell growth signals (like those provided by Pten deletion) so that carbon sources can be used for ATP production rather than for cell growth. The liver Pten deletion animals presented a liver cancer phenotype with a two-phased progression from fatty liver to HCC. We are using this model to study the interactions between PTEN regulated pathway and AMPK regulated energy signals in liver cancer progression. We are using both in vivo and in vitro system to study this interaction. In the in vivo system, we are using immunoflourescent techniques to evaluate the activity of AMPK and AMPK regulated signals during progression of Pten null liver phenotype development. The models generated in the in vivo experiments will be used to test the therapeutic anticancer reagents such as rapamycin and AICAR used separately or in combination.
What is the origin of liver cancer? Cancer stem cells are believed to be the origin of cancers in many tissues. In the liver, hepatocytes, oval cells as well as other cell type all possess capability of proliferation. Using different cell surface markers and our Pten deletion model, we are trying to identify the cell type that these liver cancer are originated from.
The Role of PTEN in cell Regeneration
To understand the mechanism of Pten deletion induced cell mass increase in the pancreatic cell Pten deletion model, we have shown that deletion of Pten in pancreatic cells leads to increased islet mass and better regeneration potential. We are using biochemical, genetics and immunohistological tools to study the role of mechanisms such as epithelial-mesenchymal-transition (EMT) and stem/progenitor cell in this phenotype. We use immunoflourescence and confocal microscopy techniques to study the interactions of proteins involved in this EMT process. This includes the downstream targets of PTEN regulated PI3K/AKT pathways and the TGF regulated Smad protein cascade. The knowledge of the expression levels of these proteins and their localizations in the cells relative to each other and to the actin skeleton network is crucial to our understanding on how EMT may contribute to cell regeneration.
To evaluate whether PTEN maybe targeted for b-cell regeneration therapy. We are also interested in understanding the potential therapeutic effect of inhibiting PTEN. Using a genetic approach, we are generating a model of Pten deletion in the pancreatic b-cells that can be regulated not only spatially but also temporally. We have generated PtenloxP/loxP; RIP-CreER model. Using this model, we can evaluate whether PTEN inhibition protects b-cell death or induces cell differentiation. With the information generated from this model, we are collaborating with the Islet Center in City of Hope to test the therapeutic potential of PTEN inhibition.
To determine the role of PTEN in cell differentiation Stem cell therapy holds great promises in treating type I diabetes patients. Using the Pten null ES cells we have generated, we will evaluate whether these ES cells holds greater therapeutic potential in the in vitro cell differentiation assay. This started as a collaborated project between engineer and biology in UCLA. Our goal is to define a high throughput differentiation system using nanomaterial such as polyethylene glycol-silica sol gel (Peg-Sol) and polydimethylsiloxane (PDMS), and polyacrylamide based thermal material. This work is mainly being carried on in UCLA currently.
Technologies used in the lab
Our lab uses molecular biology techniques to study genetically modified animals. We use both in vivo and in vitro system to evaluate the role of PTEN in growth, regeneration and tumrigenesis. The in vivo system includes the use of immunohistochemical and immunoflourescence techniques to assess protein expressions and localizations. The in vivo work also involves in vivo tumorigenic assays for evaluate tumor development as well as metabolic assays needed for evaluating the function of islets. The in vitro system is mainly focused on cell culturing including culturing hepatocytes and organ culture of islets. We are also trying to form a collaborated research program here to continue the ES cell differentiation work here in USC.
Dr. Bangyan Stiles received her BS in Food Chemistry from Jinan University (P.R. China), her MS in Nutrition from the University of Tennessee-Knoxville and her PhD in Nutritional Biochemistry from the University of Texas-Austin/MD Anderson Cancer Center. She completed two postdoctoral fellowships at UCLA, at the Howard Hughes Medical Research Institute and at the UCLA School of Medicine.
Prior to joining USC in December 2005, Dr. Stiles was an adjunct assistant professor in molecular and medical pharmacology at the UCLA School of Medicine. She is currently an assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy.
Ding W,You H,Dang H,LeBlanc F,Galicia V,Lu SC,Stiles B,Rountree CB - Epithelial-to-mesenchymal transition of murine liver tumor cells promotes invasion. - Hepatology  Sep;52(3):945-53 -Link
He L,Hou X,Kanel G,Zeng N,Galicia V,Wang Y,Yang J,Wu H,Birnbaum MJ,Stiles BL - The critical role of AKT2 in hepatic steatosis induced by PTEN loss. - Am J Pathol  May;176(5):2302-8 -Link
Galicia VA,He L,Dang H,Kanel G,Vendryes C,French BA,Zeng N,Bayan JA,Ding W,Wang KS,French S,Birnbaum MJ,Rountree CB,Stiles BL - Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. - Gastroenterology  Dec;139(6):2170-82 -Link
Rountree CB,Ding W,He L,Stiles B - Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice. - Stem Cells  Feb;27(2):290-9 -Link
Stiles BL - Phosphatase and tensin homologue deleted on chromosome 10: extending its PTENtacles. - Int J Biochem Cell Biol  Apr;41(4):757-61 -Link
Valamehr B,Jonas SJ,Polleux J,Qiao R,Guo S,Gschweng EH,Stiles B,Kam K,Luo TJ,Witte ON,Liu X,Dunn B,Wu H - Hydrophobic surfaces for enhanced differentiation of embryonic stem cell-derived embryoid bodies. - Proc Natl Acad Sci U S A  Sep 23;105(38):14459-64 -Link
Xu X,Kobayashi S,Qiao W,Li C,Xiao C,Radaeva S,Stiles B,Wang RH,Ohara N,Yoshino T,LeRoith D,Torbenson MS,Gores GJ,Wu H,Gao B,Deng CX - Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. - J Clin Invest  Jul;116(7):1843-52 -Link
Stiles BL,Kuralwalla-Martinez C,Guo W,Gregorian C,Wang Y,Tian J,Magnuson MA,Wu H - Selective deletion of Pten in pancreatic beta cells leads to increased islet mass and resistance to STZ-induced diabetes. - Mol Cell Biol  Apr;26(7):2772-81 -Link
Stanger BZ,Stiles B,Lauwers GY,Bardeesy N,Mendoza M,Wang Y,Greenwood A,Cheng KH,McLaughlin M,Brown D,Depinho RA,Wu H,Melton DA,Dor Y - Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. - Cancer Cell  Sep;8(3):185-95 -Link
Kurlawalla-Martinez C,Stiles B,Wang Y,Devaskar SU,Kahn BB,Wu H - Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. - Mol Cell Biol  Mar;25(6):2498-510 -Link