膵臓癌サブタイプにおけるADRA2Aの役割

タイトル: ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer

概要: 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=186 SRC="FIGDIR/small/584316v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): [email protected]@5579b6org.highwire.dtl.DTLVardef@1a9a000org.highwire.dtl.DTLVardef@147724a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG HighlightsO_LIADRA2A is downregulated in the basal-like/squamous PDAC while its expression is maintained in the classical/progenitor PDAC subtype C_LIO_LIUpregulated ADRA2A expression correlates with improved PDAC survival and reduced invasion in PDAC cells C_LIO_LIUpregulated ADRA2A downregulates the MYC signaling pathway and promotes the classical/progenitor gene expression profile C_LIO_LIUpregulated ADRA2A induces a unique metabolic signature characterized by diminished amino acid and carnitine/acylcarnitine metabolism, resembling the classical/progenitor PDAC subtype C_LI