The tumor microenvironment (TME) is recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escape, and distant metastasis, thereby substantially impacting the future development of frontline interventions in clinical oncology. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of sterile inflammation and infection. We recently demonstrated that RAGE plays a unique oncogenetic role in pancreatic ductal adenocarcinoma (PDAC). We demonstrated that: 1) RAGE was highly expressed in mouse and human PDAC; 2) Global ablation of RAGE in mice prevented pancreatic cancer growth in a genetically-modified spontaneous mouse model (Pdx1-Cre;K-RasG12D/+;RAGE-/-) and a xenograft mouse model; 3) RAGE was essential for oncogenic K-Ras-mediated hypoxic signaling in PDAC development; and 4) The mechanism by which this occurs in part involves inflammatory response-associated metabolic changes, cell death-promoting limitations in autophagy, and a reduction in the accumulation of myeloid-derived suppressor cells and regulatory T cells. These exciting findings raise several important questions regarding RAGE's novel role in PDAC. We hypothesize that RAGE expression in multiple components of the TME is critical for PDAC development and therapy resistance. We will pursue the following aims.
Aim 1 : identify RAGE as a critical receptor of nuclear danger signal in the TME;
Aim 2 : define the cell-specific role of RAGE in the TME;
and Aim 3 : investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in different tumor models in mice. The completion of these exciting studies will provide new insights into our understanding of the TME and guide future development of RAGE-based novel therapeutic strategies for PDAC patients.

Public Health Relevance

Significant scientific progress has been made in the last decade towards understanding the biology and natural history of pancreatic ductal adenocarcinoma (PDAC); major clinical advances, however, have not occurred. We postulate that RAGE is a novel oncogene and therapeutic target in the tumor microenvironment of PDAC. Our proposal will provide new insights into our understanding of the pathophysiology of PDAC and may lead to new therapeutic strategies to treat this lethal disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA211070-02
Application #
9502943
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Isaacs, Jennifer S
Project Start
2017-06-08
Project End
2022-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Surgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wang, Ding; Xie, Nan; Gao, Wanli et al. (2018) The ferroptosis inducer erastin promotes proliferation and differentiation in human peripheral blood mononuclear cells. Biochem Biophys Res Commun 503:1689-1695
Song, Xinxin; Zhu, Shan; Xie, Yangchun et al. (2018) JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology 154:1480-1493
Kang, Rui; Zhu, Shan; Zeh, Herbert et al. (2018) The STING-STAT6 pathway drives Cas9-induced host response in human monocytes. Biochem Biophys Res Commun 506:278-283
Li, Changfeng; Zhang, Ying; Cheng, Xing et al. (2018) PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Dev Cell 46:441-455.e8
Deng, Wenjun; Zhu, Shan; Zeng, Ling et al. (2018) The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. Cell Rep 24:366-378
Chen, Ruochan; Zhu, Shan; Fan, Xue-Gong et al. (2018) High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis. Hepatology 67:1823-1841
Song, Xinxin; Zhu, Shan; Chen, Pan et al. (2018) AMPK-Mediated BECN1 Phosphorylation Promotes Ferroptosis by Directly Blocking System Xc- Activity. Curr Biol 28:2388-2399.e5
Zeng, Ling; Kang, Rui; Zhu, Shan et al. (2017) ALK is a therapeutic target for lethal sepsis. Sci Transl Med 9:
Kang, Rui; Xie, Yangchun; Zhang, Qiuhong et al. (2017) Intracellular HMGB1 as a novel tumor suppressor of pancreatic cancer. Cell Res 27:916-932
Xie, Yangchun; Zhu, Shan; Zhong, Meizuo et al. (2017) Inhibition of Aurora Kinase A Induces Necroptosis in Pancreatic Carcinoma. Gastroenterology 153:1429-1443.e5

Showing the most recent 10 out of 11 publications