Pancreatic Cancer Stem Cells Co-Expressing SOX2, OCT4, and TERT^high Represent an Aggressive Subpopulation

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Molecular Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) aggressiveness is associated with cancer stem cells (CSCs) and telomerase activity.
• The precise mechanism linking CSCs and telomerase in PDAC remains incompletely understood.

Purpose of the Study:

• To elucidate the mechanism connecting CSCs and telomerase activity in PDAC.
• To identify and characterize aggressive CSC-like subpopulations in PDAC.
• To explore potential therapeutic vulnerabilities within these subpopulations.

Main Methods:

• Engineered dual transcriptional reporters (SORE6-GFP and TERT-BFP) to isolate specific cell subpopulations.
• Utilized Fluorescence-Activated Cell Sorting (FACS) for cell isolation.
• Performed functional assays, RNA sequencing (RNA-seq), and network analysis.

Main Results:

• Identified a SOX2⁺OCT4⁺TERT^high subpopulation (~9%) enriched in pluripotency markers and exhibiting heightened proliferative, migratory, and invasive capacities.
• Clinically, co-expression of high SOX2/OCT4/TERT levels in tumors correlated with reduced overall survival.
• Transcriptomic analysis revealed enrichment of KRAS, telomere maintenance, epithelial-mesenchymal transition, and developmental pathways (WNT, Hedgehog) in the aggressive subpopulation.
• Network analysis identified actionable vulnerabilities in NF-κB, WNT, and telomerase inhibition pathways.

Conclusions:

• Defined an aggressive, pluripotency-driven cancer stem cell-like state in PDAC associated with high telomerase (TERT) activity.
• This TERT-high CSC state is linked to poor patient survival and exhibits specific pathway enrichments.
• Suggests targeting TERT-high dependencies as a potential therapeutic strategy for PDAC.