This ongoing project utilizes omics-based strategies for investigating the underlying mechanisms of pancreatic cancer progression and disease aggressiveness to identify candidate therapeutic targets. In one of our studies we tried to attain a comprehensive molecular insight into tumors with high- and low-MIF expression and to identify key MIF-signaling pathways that drive tumor progression, we analyzed the expression of coding and non-coding genes in high (median) and low (less than median) MIF-expressing tumors in multiple cohorts of PDAC patients. The identified key genes and pathways were linked to patients' survival and were mechanistically, functionally and clinically characterized using cell lines, genetically engineered mouse model and PDAC patient cohorts. We reported mechanistic, functional and clinical evidence of a novel MIF-driven signaling pathway that inhibits a previously undescribed potential tumor suppressor, nuclear-receptor-subfamily-3, group-C, member-2 (NR3C2), leading to enhanced disease aggressiveness and poorer survival in PDAC. Mechanistically, MIF upregulated miR-301b, which then targeted and suppressed NR3C2 expression. Tumors with a higher MIF expression showed an elevated miR-301b and a reduced NR3C2 expression. Additionally, patients with a lower NR3C2 expression in tumors showed poorer survival in multiple independent cohorts of PDAC patients. These findings discovered a key MIF-induced signaling pathway, which enhances tumor progression and disease aggressiveness in PDAC. This study also identified NR3C2, a mineralocorticoid receptor gene, as a putative inhibitor of disease progression. We are currently investigating the mechanistic role of NR3C2 in PDAC. Furthermore, in our initial effort to characterize tumors from early stage resected PDAC patients with markedly different survival, we compared gene expression profiles in tumors from early stage PDAC cases with extremely poor survival (less than 7 months) and those surviving 2 years or more following surgical resection. Inflammatory gene network dominated among 1,820 differentially expressed genes between the two groups. A lower expression of NOSTRIN was associated with significantly poor survival indicating its potential tumor inhibitory role in disease progression. NOSTRIN inactivated endothelial NOS (eNOS/NOS3) and inhibited the production of nitric oxide (NO). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC. Our findings are consistent with the hypothesis that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. We are continuing our investigation into the NO-dependent and NO-independent mechanistic role of NOSTRIN in PDAC. As mentioned earlier, molecular subgroups of pancreatic ductal adenocarcinoma have been reported based on the difference in genomic, transcriptomics and metabolic profiling, however, specific molecular targets with therapeutic significance in these subgroups are yet to be clearly defined. Our ongoing study is investigating a highly aggressive subgroup to define key mechanisms driving tumor progression and disease aggressiveness that may be targeted with potential therapeutic significance. In our metabolomic studies, we have shown that impairment in a lipolytic pathway involving lipases and a unique set of free fatty acids, may play an important role in the development and progression of pancreatic cancer and provide potential targets for therapeutic intervention. We are currently investigating the role of inflammatory signaling pathways in the regulation of metabolic reprogramming in pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011162-10
Application #
9779815
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Wang, Jian; Hussain, S Perwez (2017) NO(•) and Pancreatic Cancer: A Complex Interaction with Therapeutic Potential. Antioxid Redox Signal 26:1000-1008
Wang, Jian; Yang, Shouhui; He, Peijun et al. (2016) Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer. Clin Cancer Res 22:5992-6001
Hussain, S Perwez (2016) Pancreatic Cancer: Current Progress and Future Challenges. Int J Biol Sci 12:270-2
Budhu, Anuradha; Terunuma, Atsushi; Zhang, Geng et al. (2014) Metabolic profiles are principally different between cancers of the liver, pancreas and breast. Int J Biol Sci 10:966-72
Zhang, Geng; He, Peijun; Gaedcke, Jochen et al. (2013) FOXL1, a novel candidate tumor suppressor, inhibits tumor aggressiveness and predicts outcome in human pancreatic cancer. Cancer Res 73:5416-25
Zhang, Geng; He, Peijun; Tan, Hanson et al. (2013) Integration of metabolomics and transcriptomics revealed a fatty acid network exerting growth inhibitory effects in human pancreatic cancer. Clin Cancer Res 19:4983-93
Zhang, Geng; Schetter, Aaron; He, Peijun et al. (2012) DPEP1 inhibits tumor cell invasiveness, enhances chemosensitivity and predicts clinical outcome in pancreatic ductal adenocarcinoma. PLoS One 7:e31507