Pancreatic Ductal Adenocarcinoma (PDA) is the 4th leading cause of cancer deaths in both men and women in the US. There has been very little progression in the development of treatments for PDA in the past decade, hence the need for new therapy is crucial. In order to improve the existing chemotherapy arsenal, we need to understand the biology of PDA better. Interestingly, 60 to 90 percent of pancreatic tumor mass is comprised of stroma, suggesting that tumor microenvironment may play an important role in cancer progression and metastasis.
Our lab identified Annexin A2 (ANXA2) as a protein that plays a role in metastasis and invasion of PDA. The expression and localization of ANXA2 changes with progression of pancreatic cancer; from low, mostly cytosolic expression in premalignant lesions; to high, plasma membrane expression in PDA. We have also showed that the translocation of ANXA2 to cell surface is phosphorylation dependent, specifically on Tyrosine 23 (Zheng L., et al. Tyrosine 23 phosphorylation-dependent cell-surface localization of Annexin A2 is required for invasion and metastases of pancreatic cancer. PLoS One. 2011; 6(4):e19390). The close proximity of plasma membrane ANXA2 to the tumor microenvironment is of interest to us, as it proposes a cross-talk between the stroma and cancer cells mediated by ANXA2.
My thesis project will focus on understanding specific signaling pathways within the tumor microenvironment and their role in regulation of ANXA2. This knowledge could then be utilized to develop novel therapeutic agents for treatment of pancreatic cancer.
- Sequential treatment with a listeria-based vaccine and PD-1 blockade antibody improves survival in a murine model of pancreatic ductal adenocarcinoma. V. Kim · K. Foley · K. Soares · A. Rucki · P. Lauer · D. Brockstedt · C. Wolfgang · E. Jaffee · L. Zheng. HPB 18:e45-e46 · March 2016 DOI: 10.1016/j.hpb.2016.02.113
- TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner.Soares KC, Rucki AA, Kim V, Foley K, Solt S, Wolfgang CL, Jaffee EM, Zheng L. Oncotarget. 2015 Dec 15;6(40):43005-15. doi: 10.18632/oncotarget.5656.PMID:26515728
- Semaphorin 3D autocrine signaling mediates the metastatic role of annexin A2 in pancreatic cancer. Foley K, Rucki AA, Xiao Q, Zhou D, Leubner A, Mo G, Kleponis J, Wu AA, Sharma R, Jiang Q, Anders RA, Iacobuzio-Donahue CA, Hajjar KA, Maitra A, Jaffee EM, Zheng L. Sci Signal. 2015 Aug 4;8(388):ra77. doi: 10.1126/scisignal.aaa5823.PMID:26243191
- Targeting Sema3D in pancreatic cancer: A novel therapeutic strategy. Adrian Gerard Murphy · Jennifer Kleponis · Agnieszka Rucki · Elizabeth Jaffee · Lei Zheng · Kelly Foley. May 2015Conference: ASCO 2015, At Chicago, Volume: J Clin Oncol 33, 2015 (suppl; abstr 4129).
- PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. Soares KC, Rucki AA, Wu AA, Olino K, Xiao Q, Chai Y, Wamwea A, Bigelow E, Lutz E, Liu L, Yao S, Anders RA, Laheru D, Wolfgang CL, Edil BH, Schulick RD, Jaffee EM, Zheng L.J Immunother. 2015 Jan;38(1):1-11. doi: 10.1097/CJI.0000000000000062.PMID:25415283
- Keenan BP, Saenger Y, Kafrouni MI, Leubner A, Lauer P, Maitra A, Rucki AA, Gunderson AJ, Coussens LM, Brockstedt DG, Dubensky TW Jr, Hassan R, Armstrong TD, Jaffee Listeria vaccine and depletion of T-regulatory cells activate immunity against early stage pancreatic intraepithelial neoplasms and prolong survival of mice. EM.Gastroenterology. 2014 Jun;146(7):1784-94.e6. doi: 10.1053/j.gastro.2014.02.055. Epub 2014 Mar 6.PMID:24607504
- Donger Zhou · Qian Xiao · Agnieszka Rucki · Guanglan Mo · Lanqing Huang · Anirban Maitra · Elizabeth Jaffee · Lei Zheng Abstract 3935: AnnexinA2 regulates invasion and metastasis of pancreatic ductal adenocarcinoma through Semaphorin3d. Kelly Foley · Cancer Research 73(8 Supplement):3935-3935 August 2013
- Rucki AA, Zheng L. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J Gastroenterol. 2014 Mar 7;20(9):2237-46. doi: 10.3748/wjg.v20.i9.2237. Review.PMID:24605023
- Van Meerbeke JP, Gibbs RM, Plasterer HL, Miao W, Feng Z, Lin MY, Rucki AA, Wee CD, Xia B, Sharma S, Jacques V, Li DK, Pellizzoni L, Rusche JR, Ko CP, Sumner CJ. The DcpS inhibitor RG3039 improves motor function in SMA mice. Hum Mol Genet. 2013 Oct 15;22(20):4074-83. doi: 10.1093/hmg/ddt257. Epub 2013 May 31.PMID:23727836