This is a competitive renewal of the originally funded R01 that was focused on dissecting Annexin A2 mediated mechanisms for the invasion and metastasis of pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the major causes of death from malignant diseases. The poor prognosis of PDAC is attributed to early onset of metastasis and lack of effective treatments for PDACs. The tumor microenvironment (TME) of PDAC is believed to hold a key for overcoming the challenge of treating PDAC. Previously, we showed that tyrosine phosphorylation of Annexin A2 is essential for PDAC invasion and metastasis. We further discovered that Annexin A2 controls the secretion of Semaphorin 3D (Sema3D) and the autocrine effect of Sema3D on PDAC invasion and metastasis through binding to its receptor, Plexin D1/Neuropilin-1 (PlxnD1/NrP1). Interestingly, Sema3D, PlxnD1, and NrP1 all belong to the nerve axon guidance protein family, which is among the most frequently altered gene families in PDACs. The neuronal component of the TME in PDACs cannot be negligible as perineural invasion (PNI) is an important pathological characteristic in many malignancies, particularly PDAC. Semaphorins and plexins have also been implicated to regulate immune functions by controlling differentiation and trafficking of macrophages. Accumulated evidence has suggested that macrophages promote the development of the acinar to ductal metaplasia (ADM), which is thought to be a mechanism underlying the initiation of PDACs. Therefore, we propose to test the hypothesis that the interaction between the tumor cells and nerves plays an essential role in promoting ADM, growth, invasion, and metastasis of PDAC. First, this new project will dissect a paracrine Sema3D-PlxnD1 signaling pathway that mediates the PNI and subsequent metastasis of PDAC. Second, the project will study the nerve-derived Sema3D in controlling PDAC development through the PlxnD1 receptor on tumor cells in a mutant Kras- dependent manner. It will examine whether the Warburg effect induced by the Sema3D/PlxnD1-mutant Kras- ARF-GTP signaling cascade will affect the function of macrophages in vitro and whether tumor associated macrophages (TAM) will be reprogrammed in vivo when Sema3D is tissue-specifically knocked out from sensory nerves. Third, this project will investigate the role of Sema3D and the genetic alterations of the axon guidance pathway in vivo in pro-cancerous inflammatory response and PDAC development in both mouse models of PDAC and human PDAC specimens. The relationship between the expression of axon guidance molecules in pancreatic premalignant and malignant epithelia, in intra-pancreatic nerves, and in immune cells and the quantity and distribution of macrophages and other immune cells will be assessed. 1

Public Health Relevance

Peri-neural invasion is an important pathological characteristic in many malignancies, particularly pancreatic cancer. Previous reports have also suggested that nerves play a central role in promoting the inflammatory process in the pancreas. Therefore, this project will investigate the mechanistic basis underlying the interaction between the tumor cells and nerves and interrogate how this molecular mechanism controls pro-cancerous inflammatory process and promotes the growth, invasion, and metastasis of pancreatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Snyderwine, Elizabeth G
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Saung, May Tun; Muth, Stephen; Ding, Ding et al. (2018) Targeting myeloid-inflamed tumor with anti-CSF-1R antibody expands CD137+ effector T-cells in the murine model of pancreatic cancer. J Immunother Cancer 6:118
Zhang, Jiajia; Quadri, Shafat; Wolfgang, Christopher L et al. (2018) New Development of Biomarkers for Gastrointestinal Cancers: From Neoplastic Cells to Tumor Microenvironment. Biomedicines 6:
Zhang, Jiajia; Wolfgang, Christopher L; Zheng, Lei (2018) Precision Immuno-Oncology: Prospects of Individualized Immunotherapy for Pancreatic Cancer. Cancers (Basel) 10:
Saung, May Tun; Zheng, Lei (2017) Current Standards of Chemotherapy for Pancreatic Cancer. Clin Ther 39:2125-2134
Murphy, Adrian G; Foley, Kelly; Rucki, Agnieszka A et al. (2017) Stromal Annexin A2 expression is predictive of decreased survival in pancreatic cancer. Oncotarget 8:106405-106414
Zheng, Lei (2017) PD-L1 Expression in Pancreatic Cancer. J Natl Cancer Inst 109:
Pea, Antonio; Yu, Jun; Rezaee, Neda et al. (2017) Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas. Ann Surg 266:133-141
Rucki, Agnieszka A; Xiao, Qian; Muth, Stephen et al. (2017) Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment. Mol Cancer Ther 16:2399-2409
Zhang, Meng-Wen; Fujiwara, Kenji; Che, Xu et al. (2017) DNA methylation in the tumor microenvironment. J Zhejiang Univ Sci B 18:365-372
Shrestha, Bikram; Sun, Yifei; Faisal, Farzana et al. (2017) Long-term survival benefit of upfront chemotherapy in patients with newly diagnosed borderline resectable pancreatic cancer. Cancer Med 6:1552-1562

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