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Douglas Stairs
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Title Assistant Professor
Institution College of Medicine
Department Pathology
Address 500 University Drive Hershey PA 17033
 Mailbox: HO83
Telephone 7175316725
Email
Background
PREFERRED TITLE/ROLE:

Assistant Professor of Pathology, Pharmacology, and Biochemistry & Molecular Biology

SECONDARY APPOINTMENT(S)/ INSTITUTE(S)/ CENTER(S):

Pharmacology, Penn State Hershey Cancer Institute

GRADUATE PROGRAM AFFILIATIONS:

Biomedical Studies

EDUCATION:

Ph.D., University of Pennsylvania, 2004
Postdoctoral Training, University of Pennsylvania, 2005-2010

NARRATIVE:

The worldwide prevalence of esophageal cancer varies greatly with the highest rates found in Asia. In the United States the two most common types of esophageal cancers are squamous cell carcinoma (ESCC) and adenocarcinoma (EAC). In 2010 there were about 16,600 new cases of esophageal cancer diagnosed in the US and approximately 14,500 deaths will occur from esophageal cancer. In fact, since patients are typically diagnosed at a late stage of the disease, overall five year survival is approximately 18%. Given the poor survival rate, the advanced stage of the disease at diagnosis and the increasing frequency of ESCC (worldwide) and EAC (US), it is increasingly important to understand the molecular mechanisms of initiation of these tumors as well as the genes and pathways involved.

ESCC

ESCC is highlighted by the interplay of classical oncogenes and tumor suppressor genes. We have found that p120ctn, a tumor suppressor gene, is mislocalized to the cytoplasm or lost in nearly all human ESCC. This initial observation has been pursued in a genetically engineered mouse model through tissue-specific ablation of p120ctn, resulting in inflammation and cancer in the esophagus. Loss of p120ctn in the mouse esophagus results in tumor development that is nearly indistinguishable from human ESCC. Analyses of the development of these tumors in the mouse had revealed an important role for the immune system. The presence of immune cells in the tumor microenvironment is necessary for invasion of the epithelium and the activation of fibroblasts in the tumor microenvironment. The recruitment of these cells is dependent on NFkB activation in the epithelium, subsequent to p120ctn loss. The mechanism of NFkB activation is an area of current research in the laboratory. By identifying the processes by which NFkB signaling is activated we hope to identify potential therapeutic targets for ESCC. To that end, we employ two-dimensional as well as three-dimensional culturing techniques to dissect cellular crosstalk pathways. These in vitro experiments compliment in vivo experiments involving xenograft and genetically engineered mouse models of esophageal cancer.

EAC

Barrett’s esophagus (BE) is a highly prevalent premalignant condition whereby the normal stratified squamous esophageal epithelium undergoes a transdifferentiation process resulting in a simple columnar epithelium reminiscent of the small intestine. Barrett’s esophagus is a precursor lesion to esophageal adenocarcinoma (EAC), which has the highest rate of increase in incidence of any cancer type in the United States. Changes in BE are associated with epithelial exposure to acid and bile salts as a result of gastroesophageal reflux disease (GERD). Despite this well-defined epidemiologic association between acid reflux and BE, the genetic changes that induce this transdifferentiation process in esophageal keratinocytes are poorly defined. Our previous work has begun to identify pathways capable of inducing this transdifferentiation process. Having identified the transcription factors c-myc and Cdx1 as inducers of Barrett’s esophagus, we now wish to identify genes and biomarkers for the progression of BE to EAC.

This will be accomplished in a collaborative effort with GI surgeons providing surgical samples for our research. Our goals will be to establish new cell lines of BE and EAC, define the molecular and genetic changes between BE and EAC and to select and test candidate genes for their ability to mark those cells that are poised to develop into EAC before they undergo transformation. In a similar manner we will identify those genes and signaling pathways that are involved in the transformation process. Ultimately, these data will allow for biomarker development to predict the risk a Barrett’s esophagus patient has to develop EAC. As well, this research will allow for the development of targeted therapeutics for the treatment of EAC.

Current and Possible Future Research Projects:

Identify the factors involved in NFkB activation
Understand the intercellular mechanisms by which p120ctn loss leads to transformation
Explore novel mouse models of esophageal cancer
Identify biomarkers for the progression of Barrett’s esophagus to Esophageal Adenocarcinoma
Identify pathways involved in the development of Esophageal Adenocarcinoma amenable to therapeutic intervention

These projects will be explored using genetic modeling in tissue culture and mouse model systems combined with biochemical, pharmacologic and cell & molecular biology techniques.
Publications
1. Chen CC, Stairs DB, Boxer RB, Belka GK, Horseman ND, Alvarez JV, Chodosh LA. Autocrine prolactin induced by the Pten-Akt pathway is required for lactation initiation and provides a direct link between the Akt and Stat5 pathways. Genes Dev. 2012 Oct 1; 26(19):2154-68.
  View in: PubMed
 
2. Bhardwaj A, McGarrity TJ, Stairs DB, Mani H. Barrett's Esophagus: Emerging Knowledge and Management Strategies. Patholog Res Int. 2012; 2012:814146.
  View in: PubMed
 
3. Kong J, Crissey MA, Stairs DB, Sepulveda AR, Lynch JP. Cox2 and ß-catenin/T-cell factor signaling intestinalize human esophageal keratinocytes when cultured under organotypic conditions. Neoplasia. 2011 Sep; 13(9):792-805.
  View in: PubMed
 
4. Stairs DB, Bayne LJ, Rhoades B, Vega ME, Waldron TJ, Kalabis J, Klein-Szanto A, Lee JS, Katz JP, Diehl JA, Reynolds AB, Vonderheide RH, Rustgi AK. Deletion of p120-catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Cancer Cell. 2011 Apr 12; 19(4):470-83.
  View in: PubMed
 
5. Chen CC, Boxer RB, Stairs DB, Portocarrero CP, Horton RH, Alvarez JV, Birnbaum MJ, Chodosh LA. Akt is required for Stat5 activation and mammary differentiation. Breast Cancer Res. 2010; 12(5):R72.
  View in: PubMed
 
6. Ohashi S, Natsuizaka M, Wong GS, Michaylira CZ, Grugan KD, Stairs DB, Kalabis J, Vega ME, Kalman RA, Nakagawa M, Klein-Szanto AJ, Herlyn M, Diehl JA, Rustgi AK, Nakagawa H. Epidermal growth factor receptor and mutant p53 expand an esophageal cellular subpopulation capable of epithelial-to-mesenchymal transition through ZEB transcription factors. Cancer Res. 2010 May 15; 70(10):4174-84.
  View in: PubMed
 
7. Kong J, Stairs DB, Lynch JP. Modelling Barrett's oesophagus. Biochem Soc Trans. 2010 Apr; 38(2):321-6.
  View in: PubMed
 
8. Stairs DB, Kong J, Lynch JP. Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. Prog Mol Biol Transl Sci. 2010; 96:231-70.
  View in: PubMed
 
9. Bass AJ, Watanabe H, Mermel CH, Yu S, Perner S, Verhaak RG, Kim SY, Wardwell L, Tamayo P, Gat-Viks I, Ramos AH, Woo MS, Weir BA, Getz G, Beroukhim R, O'Kelly M, Dutt A, Rozenblatt-Rosen O, Dziunycz P, Komisarof J, Chirieac LR, Lafargue CJ, Scheble V, Wilbertz T, Ma C, Rao S, Nakagawa H, Stairs DB, Lin L, Giordano TJ, Wagner P, Minna JD, Gazdar AF, Zhu CQ, Brose MS, Cecconello I, Jr UR, Marie SK, Dahl O, Shivdasani RA, Tsao MS, Rubin MA, Wong KK, Regev A, Hahn WC, Beer DG, Rustgi AK, Meyerson M. SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas. Nat Genet. 2009 Nov; 41(11):1238-42.
  View in: PubMed
 
10. Stairs DB, Ohashi S, Nakagawa H. Cellular biometrics in the postgenomics era. Cancer Biol Ther. 2008 Nov; 7(11):1756-7.
  View in: PubMed
 
11. Kalabis J, Oyama K, Okawa T, Nakagawa H, Michaylira CZ, Stairs DB, Figueiredo JL, Mahmood U, Diehl JA, Herlyn M, Rustgi AK. A subpopulation of mouse esophageal basal cells has properties of stem cells with the capacity for self-renewal and lineage specification. J Clin Invest. 2008 Dec; 118(12):3860-9.
  View in: PubMed
 
12. Stairs DB, Nakagawa H, Klein-Szanto A, Mitchell SD, Silberg DG, Tobias JW, Lynch JP, Rustgi AK. Cdx1 and c-Myc foster the initiation of transdifferentiation of the normal esophageal squamous epithelium toward Barrett's esophagus. PLoS One. 2008; 3(10):e3534.
  View in: PubMed
 
13. Okawa T, Michaylira CZ, Kalabis J, Stairs DB, Nakagawa H, Andl CD, Johnstone CN, Klein-Szanto AJ, El-Deiry WS, Cukierman E, Herlyn M, Rustgi AK. The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. Genes Dev. 2007 Nov 1; 21(21):2788-803.
  View in: PubMed
 
14. Sarkisian CJ, Keister BA, Stairs DB, Boxer RB, Moody SE, Chodosh LA. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nat Cell Biol. 2007 May; 9(5):493-505.
  View in: PubMed
 
15. Takaoka M, Kim SH, Okawa T, Michaylira CZ, Stairs DB, Johnstone CN, Andl CD, Rhoades B, Lee JJ, Klein-Szanto AJ, El-Deiry WS, Nakagawa H. IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer Biol Ther. 2007 Apr; 6(4):534-40.
  View in: PubMed
 
16. Boxer RB, Stairs DB, Dugan KD, Notarfrancesco KL, Portocarrero CP, Keister BA, Belka GK, Cho H, Rathmell JC, Thompson CB, Birnbaum MJ, Chodosh LA. Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation. Cell Metab. 2006 Dec; 4(6):475-90.
  View in: PubMed
 
17. Stairs DB, Notarfrancesco KL, Chodosh LA. The serine/threonine kinase, Krct, affects endbud morphogenesis during murine mammary gland development. Transgenic Res. 2005 Dec; 14(6):919-40.
  View in: PubMed
 
18. Chodosh LA, Gardner HP, Rajan JV, Stairs DB, Marquis ST, Leder PA. Protein kinase expression during murine mammary development. Dev Biol. 2000 Mar 15; 219(2):259-76.
  View in: PubMed
 
19. Chodosh LA, D'Cruz CM, Gardner HP, Ha SI, Marquis ST, Rajan JV, Stairs DB, Wang JY, Wang M. Mammary gland development, reproductive history, and breast cancer risk. Cancer Res. 1999 Apr 1; 59(7 Suppl):1765-1771s; discussion 1771s-1772s.
  View in: PubMed
 
20. Stairs DB, Perry Gardner H, Ha SI, Copeland NG, Gilbert DJ, Jenkins NA, Chodosh LA. Cloning and characterization of Krct, a member of a novel subfamily of serine/threonine kinases. Hum Mol Genet. 1998 Dec; 7(13):2157-66.
  View in: PubMed
 
 
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Co-Authors  
El-Deiry, Wafik
Mcgarrity, Thomas
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