ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

Deciphering The Complex Biological Interactions Of Nitric Oxide In Cancer.

NO• is a free radical and is involved in a number of critical physiological processes including vasodilation, neurotransmission, immune regulation and inflammation. There are convincing evidence suggesting a role of NO• in the development and progression of different cancer types. However, the role of NO• in tumorigenesis is highly complex and both pro- and anti-neoplastic functions have been reported, which largely depends on the amount of NO•, cell types, cellular microenvironment, its interaction with other reactive species and presence of metals. An interesting interaction occurs between NO• and p53 tumor suppressor, in which NO•-induced DNA damage causes the stabilization and accumulation of p53, which in turn, transrepresses inducible nitric oxide synthase (NOS2) in a negative feedback loop. In chronic inflammatory diseases, for example ulcerative colitis, NO• induces p53 stabilization and the initiation of DNA-damage response pathway, and also generation of p53 mutation and subsequent clonal selection of p53 mutant cells. Genetic deletion of NOS2 in p53-deficient mice can either suppress or enhance lymphomagenesis depending on the inflammatory microenvironment. These findings highlight the importance of understanding the complex biological interaction of NO• in the context of the molecular makeup of each individual cancer to design NO•-targeted treatment strategies.