Fibromodulin promotes PDAC progression through multifaceted regulation of tumor growth pathways: Implications for...

Therapeutic progress in pancreatic ductal adenocarcinoma (PDAC) has been slow. A key factor contributing to this lethal disease's progression is excessive extracellular matrix (ECM) deposition, as highlighted in numerous studies. Fibromodulin (FMOD), a significant ECM component, is speculated to play a crucial role in PDAC, however detailed studies on this are lacking. As such, our study evaluated the functional importance of FMOD in the context of PDAC to understand its mechanistic role.

Through systematic bioinformatics analysis and tissue microarray analysis, the expression of FMOD in PDAC was investigated. Further, the study delved into the specific roles FMOD plays in PDAC development both in vitro and in vivo using loss-of-function and gain-of-function strategies. Additionally, the influence of FMOD on the differential metabolites in the serum of PDAC mice was analyzed using metabolomics.

FMOD is highly expressed in PDAC (fold change = 7.7, p < 0.05) and is associated with poor clinical outcomes. FMOD significantly promotes the proliferation, migration, and invasion of PDAC cells while inhibiting apoptosis. Mechanistically, FMOD expression is associated with activation of the TGFβ/SMAD2/3 and EGFR-mediated PI3K/AKT/mTOR signaling pathways. Additionally, Metabolomic analysis demonstrated that FMOD elevates prostaglandin levels by upregulating key arachidonic acid-metabolizing enzymes (cPLA2 and COX-2).

FMOD plays critical roles in the development and progression of PDAC. These findings highlight FMOD as a candidate prognostic marker and suggest that targeting FMOD merits further exploration in PDAC.