Bangyan L. Stiles, PhD
Professor and Vice ChairPharmacology and Pharmaceutical Sciences
- Cancer Cell Biology
- Cancer Genetics
- Cell Cycle
- Growth & Proliferation
- Cell Death
- Signal Transduction
- Stem Cell Biology
- Developmental Biology
- Cancer Biology
- Islet Biology
- Lipid Metabolism
- 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
The primary focus of my laboratory is to explore the molecular bases for the normal and pathological processes of human health. The knowledge gained from such discovery is fundamental in product and therapeutic development aimed at improving human health. I use in vivo approaches to understand the two sides of the growth signal regulation: lack of which leads to degeneration whereas too much results in cancer development. With the intact system and the ability to manipulate signalings throughout the aging process, I have the advantage to view the signaling interactions in multiple cell settings as well as through different ages. Specifically, I focus on two projects, one is to understand how aged pancreatic beta-cells lose their response to the growth/regeneration signal and how this relates to the onset of diabetes; the other is to investigate how altered growth signals promote tumor transformation in the liver. I targeted pancreatic beta-cells because lack of regeneration in beta-cells is a major contributor to diabetes, a disease that affects 6-10% US population. The liver is targeted to study the cancer spectrum because of the high lethality of liver cancer worldwide and in the US.
1) Cancer Biology
Significance: Cancer is classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes over the last few decades. However, genetic events alone are not sufficient to explain the progression and development of cancers; tumor development is often associated with metabolic and immunological changes. A fundamental question in the cancer field is whether and how metabolic changes drive the development of cancer. My lab focuses on lipid metabolism because one out of three cancer deaths are attributed to occur in individuals who are overweight or obese. My lab was the first to explore the molecular link between tumor suppressor/oncogenes and lipid metabolism. In 2010, our landmark paper for the first time unequivocally showed that fat accumulation is required for tumor growth. Since then, our work has built upon this fundamental observation to uncover how lipid accumulation leads to cancer formation. This research has led to the discovery of novel signals involved in this tumor promoting process and new effort in therapeutic development aimed to intervene in the metabolic signals for cancer treatment.
Recent works from my lab can be highlighted with three major discoveries: discovering the critical signal that mediates the steatosis induced tumorigenesis; elucidating the novel mechanisms by which tumor suppressor/oncogenes control lipid metabolism; and establishing the role of PI3K signal in mitochondrial bioenergetics. Our work explored the role of cellular stress response in tumorigenesis as fat accumulation is a tremendous stress to the cells. These metabolic stress leads to cellular damage and establishes niche activation signals for the transformed tumor initiating cells (TIC) to grow and become the tumor. Our current work includes designing and testing novel small molecule drugs that target the mechanisms that we have discovered in the lab.
2) Aging and regeneration
Significance: Like obesity, age is also a confounding factor in a number of other diseases including cancer and diabetes. My second project focuses on defining the molecular differences between young and aged tissues/cells using pancreatic beta-cells as a model. Organisms age via slowing of their tissue regeneration. In some individuals, this process appears to be accelerated, leading to pathological aging and disease states such as Alzheimer’s and Parkinson’s diseases. Pancreatic beta-cells are one of the first cell types to experience an aging-induced decay of proliferation, making them a good model for studying the molecular mechanisms associated with aging. Work from my lab had established that adult pancreatic beta-cells enter a state of no-activity (quiescence) in an age-dependent manner (5, 11, 15, 25, 31). This age-related loss of regeneration in beta-cells is a major contributing factor to both type I and II diabetes, diseases affecting 6-10% of the US population.
Accomplishments: By focusing on the signaling of IGF-1, a circulating hormone that declines with age, work from my lab indicates that molecules controlling cellular senescence such as p16Ink play a major role in aging of pancreatic beta-cells (11, 15). These studies for the first time established a potential molecular foundation for how hormonal changes like IGF-1 in aging individuals may control cellular growth inactivity in aging cells. Works in my lab is attempting to understand how this signaling node that we discovered respond to pathophysiological ques. While all individuals experience similar decline of circulating IGF-1, not all exhibit the same pathological phenotypes. In addition to inherent individual differences, environmental factors such as diet also plays a role. Using both genetic and dietary interventions, current work in my lab is exploring how dietary factors are interacting with genetic differences to contribute to the pathogenesis of diabetes (58).
Implications: Cellular senescence occurs in all aging tissues at varied degrees. Works from my lab established that altering cellular senescence molecular signals may be a viable approach for treating age-related degenerative diseases. The work in my lab is not only import for diabetes treatment, but also has strong implications for other age-related diseases. My future work in this area will continue to explore the molecules that control this cellular senescence process with regard to age, and will attempt to uncover marker(s) for molecular aging, enabling the development of both diagnostics and therapies.
The liver cancer project was initially supported by multiple sources including pilot grants from two program projects funded by the NIH (NCI 5U 54 CA114868 and P30DK48522) and a Zumberge interdisciplinary research grant. The sustained work to continue the project is now supported by a R01 (1R01CA154986-01) from NIH and a subcontract of a R01 (2R01CA108614-06A1) from Baylor University. Several trainees from this project are also funded through fellowship programs such as the Cellular, Biochemical and Molecular Sciences (CBM), a NIH T32 program and the California Institute for Regenerative Medicine (CIRM) training fellowships as well as USC Provost Fellowships.This pancreatic beta-cell project received Zumberg and R21 (NIDDK R21 DK075928-02S1) funding mechanisms initially and is funded by NIDDK through an R01 (NIDDK1 R01 DK084241-01A1) mechanism. In addition, the beta-cell project also receives funding through fellowship programs awarded to graduate student (NIDDK 1 R36 MD005009-01 and CBM training fellowship) who had successfully completed her training with excellent publications. The rat model initiative recently received funding from the California Institute of Regenerative Medicine (CIRM RT3-07949).
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 her postdoctoral fellowships at UCLA with the Howard Hughes Medical Research Institute and 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 a professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy.
1. Chen J., Che, C.-Y., Nguyen, C., Chen, L., Lee, K., and Stiles, B. L. (2018) Emerging Signals regulating liver tumor initiating cells. Liver Reserch 2 (2): 73-80.
2. Patil I, Sancheti H, Stiles B. L. (2018), Cadenas E. Brain metabolic and functional alterations in a liver-specific PTEN knockout mouse model. PLoS One. 2018; 13(9):e0204043. PMID: 30235271.
3. Chen CY, Chen J, He L, Stiles B. L.. (2018) PTEN: Tumor Suppressor and Metabolic Regulator. Front Endocrinol (Lausanne). 9:338. PMID: 30038596.
4. Lee, J., K. Liu, B. Stiles, and J. J. Ou. (2018) Mitophagy and Hepatic Cancer Stem Cells. Autophagy 1-6.
5. Kopp, J. L., Dubois, C. L., Schaeffer, D. F., Stiles, B. L., Valasek, M., and Sander, M. (2018) PTEN loss and Kras activation act synergistically in ductal cells to induce intraductal papillary mucinous neoplasia reminiscent of human disease Gastroenterology 154(5):1509-1523.e5. PMID: 29273451.
6. Debebe, A., Medina, V., Che, C.-Y., Mahajan, I., Jia, C., Fu, D., He, L., Zeng, N., Stiles, B. W., Chen, C.-L., Wang, M., Aggarwal, R., Peng, Z., Huang, J., Chen, J., Li, M., Dong, T., Atkins, S., Borok, Z., Machida, K., Yuan, W., Ju, C., Kahn, M., Johnson, D. and Stiles, B. L. (2017) Wnt/beta-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene 36 (43): 6020-6029. PMID: 28671671. PMCID: PMC5666317.
7. Machia, K., Ying, Q., Ou, J.J., and Stiles, B. L. (2017) Nuclear receptor 3B (NR3B): Bridging mitochondrial reprogramming and pluripotency through crosstalk with Nanog. Trends in Cell & Mol. Biol. (in press)
8. Jia, C., Medina, V., Liu, C., He, L., Qian, D., Tu, T., Okamoto, C., Stiles, B. L. (2017) Crosstalk of LKB1- and PTEN-regulated signals in liver morphogenesis and tumor development. Hepatology Comm. 1(2): 153-167. PMID: 29152604. PMCID: PMC5687583.
9. He, L., Gubbins, J., Peng, Z., Medina, V., Fei, F., Asahina, K., Wang, J., MacVeigh-Aloni, M., Petrocich, L. and Stiles, B. L. (2016) Activation of hepatic stellate cells in Pten null liver injury model. Fibrogenesis & Tissue Repair 9(1):1.
10. Johnson, D. and Stiles, B. L. (2016) Maf1, A New PTEN Target Linking RNA and Lipid Metabolism. Trends Endocrinol. Metab. In press
11. Shearn, C.T., Orlicky, D. J., Smathers-McCollough, R. L., Jiang, H., Maclean, K. L., Mercer, K. E., Stiles, B. L., Saba, L., Ronis, M. R., and Petersen, D. R. (2016) Liver-specific deletion of phosphatase and tensin homolog deleted on chromosome 10 significantly ameliorates chronic EtOH-induced increases in hepatocellular damage. Plos One 11(4):e0154152.
12. Liu Z., Patil, I. Y., Jiang T., Sacheti, H., Walsh, J. P., Stiles, B. L., Yin, F., and Cadenas, E. (2015) High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity. Plos One 10(5): e0128274.
13. Bayan, J., Peng, Z., Zeng N., He, L., Chen, J., and Stiles, B. L. (2015) Crosstalk Between Activated Myofibroblasts and β Cells in Injured Mouse Pancreas. Pancreas 44(7):1111-20.
14. Palian, B.M., Rohira, A. D., He, L., Johnson, S.A.S.., Zeng, N., Dubeau, L., Stiles, B. L., and Johnson, D. (2014) Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism. PLoS Genet 11(3): e1005055.
15. Chen, W.-T., Zhu, G., Pfaffenbach, K., Kanel, G., Stiles, B., and Lee, A. (2014) GRP78 as a regulator of liver steatosis and cancer progression mediated by loss of the tumor suppressor PTEN. Oncogene, 2013 Oct 21. doi: 10.1038/onc.2013.437. [Epub ahead of print] PMCID: PMC3994182.
16. Pulido, R., Baker,, S. J., Barata, J. T., Carracedo, A., Cid, V. M., Chin-Sang, I. D., Davé, V., den Hertog Devreotes, P., Eickholt, B. J., Eng, C., Furnari, F. B., Georgescu, M.-M., Gericke, A., Hopkins, B., Jiang, X., Lee, S.-R., Losche, M., Malaney, P., Matias-Guiu, X., Molina, M., Pandolfi, P. P., Parsons, R., Pinton, P., Rivas, C., Rocha, R. M., Rodríguez, M. S., Ross, A. H., Serrano, M., Stambolic, V., Stiles, B. L., Suzuki, A., Tan, S.-S., Tonks, N. K., Trotman, L. C., Wolff, N., Woscholski, R., Wu., H., and Leslie, N. R. (2014) A Unified Nomenclature and Amino Acid Numbering for Human PTEN. Sci. Signaling 7(332):pe15. Review.
[THIS PAPER WAS PUT TOGETHER BY THE RECOGNIZED INVESTIGATORS TO DEFINE THE EMERGING PTEN FIELD]
17. Wu, J. B., Shao, C., Li, X., Li, Q., Hu, P., Shi, C., Li, Y., Chen, Y.-T., Yin, F., Liao, C.-P., Stiles, B. L., Zhau, H. E., Shih, J. C., and Chung, L.W.K. (2014) Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis. Journal of Clinical Investigation 124:2891-2908. PMCID: PMC4071401
18. Shearn, C. T., Mercer, K. E., Orlicky, D. J., Hennings, L., Smathers-MaCullough, R. L., Stiles, B. L., Ronis, M. J., and Petersen, D. R. (2014) Short term feeding of a high fat diet exerts an additive effect on hepatocellular damage and steatosis in liver-specific Pten knockout mice. Plos One 9 (5): e96553
19. Chen, W.-T., Tseng, C.-C., Pfaffenbach, K., Kanel, G., Luo, B., Stiles, B., and Lee, A. (2014) Liver-specific Knockout of GRP94 in Mice Disrupts Cell Adhesion, Activates Liver Progenitor Cells, and Accelerates Liver Tumorigenesis. Hepatology 59(3): 947-957.
20. Yang, K.T., Bayan, J.A., Zeng, N., Aggarwal, R., He, L. Peng, Z., Kassa, A., Kim, M., Luo, Z., Shi, Z., Medina, V., Boddupally, K., and Stiles, B. L. (2014) Adult-onset deletion of Pten increases islet mass and beta cell proliferation in mice. Diabetologia 57(2):352-61 PMCID: PMC3918745.
[THIS PAPER WAS ACCOMPANIED BY AN EDITORIAL COMMENTS BY Dr. ANDREW STEWART IN THE SAME ISSUE]
21. Tsen, F., O’Brien, K., Cheng, C.-F., Chen, M., Hay, N., Stiles, B. L., Woodley, D., and Li, W. (2013) Extracellular heat shock protein 90 signals through sub-domain II and the NPVY motif of LRP-1 receptor to Akt1 and Akt2: A Circuit essential for promoting skin cell migration in vitro and wound healing in vivo. Mol. Cell. Biol. 33(24):4947-59. PMID:24126057. PMC ID: PMC3889557.
22. Zeng, N., Yang, K.T., Bayan, J. A., He, L., Aggarwal, R., Stiles, J. W., Hou, X., Medina, V., Abad, D., Palian, B.M., Al-abdulabh, I., Kandeel, F., Johnson, D.L., and Stiles B. L. (2013) PTEN controls b-cell regeneration in aging mice by regulating cell cycle inhibitor p16ink4a Aging Cell 12:1000-11 PMID: 23826727 PMCID: PMC3838454.
23. Li, Y., He, L., Zeng, N., Sahu, D., Cadenas, E., Shearn, C., Li, W., and Stiles, B. L. (2013) Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling regulates mitochondrial biogenesis and respiration via estrogen-related receptor α (ERRα). J. Biol. Chem. 288(30): 25007-24. PMID:23836899 PMCID: PMC3757167
[THIS PAPER WAS RECOMMENDED BY FACULTY 1000 at http://f1000.com/prime/718030711?subscriptioncode=ae76bc35-c999-4c2a-856a-7622fd97c033]
24. Li, C., Li, Y., He, L., Aggarwal, A., Zeng, N., Cadenas, E., and Stiles, B. L. (2013) PI3K/AKT signaling regulates bioenergetics in immortalized hepatocytes. Free Radical Biology and Medicine 60: 29-40. PMID: 23376468 PMCID: PMC3654039
25. Lin, T.-C., Chen, Y.-R., Kensicki, E., Li, A., Kong, M., Li, Y., Mohney, R., H.-M., Shen, Stiles, B. L., Mizushima, N., Lin, L.-I., and Ann, D. (2012) Autophagy: Resetting Glutamine-dependent Metabolism and Oxygen Consumption. Autophagy 2012 Oct 1;8(10):1477-93. PMID:22906967. PMCID: PMC3678231.
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