Trib3 identified as a key therapeutic target for pancreatic cancer stem cells

Background: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, exhibiting early dissemination and chemoresistance. These features are attributed to a specialized subpopulation of cancer stem cells (CSCs). Our lab has defined the cell of origin for PDAC within the pancreatic duct gland (PDG) stem cell compartment, a region crucial for epithelial renewal. Creation and maintenance of the CSC pool is hypothesized to underlie aggressive tumor biology, but transcriptional networks in this compartment remain poorly characterized. Objective: To define molecular pathways unique to pancreatic cancer stem cells (CSCs) that can be exploited as targeted therapies to eradicate CSCs while sparing normal pancreatic stem cells. Methods: Genetically engineered mouse models and single-cell RNA sequencing were used to trace and compare CSC-enriched (TTKS) and normal (TT) PDG organoids. Key findings were validated in other mouse and human PDAC models. Results: Single-cell analysis revealed broad upregulation of stem cell and CSC markers (Mthfd2, Slc7a5, Gadd45a), supporting conserved stem-like signatures in CSCs. Twelve genes were uniquely upregulated in PDAC CSCs, revealing new CSC-selective pathways. Trib3 was most strongly and widely upregulated among these, with multiple downstream regulators (beta-catenin, FOXO1, ATF4) also enriched, indicating robust Trib3-driven network activation. Conclusion: Identification of a discrete PDG stem cell origin for PDAC enables detailed interrogation of CSC biology. Our model demonstrates that PDAC CSCs activate unique survival and adaptation pathways, with Trib3 emerging as a central regulator. Collectively, this provides new mechanistic insight and positions Trib3 as a compelling CSC-targeted therapeutic candidate.​​ Work is going on to understand the biological role of Trib3 in progression of CSCs in PDAC.