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ecDNA-driven oncogene super-expressors shape immunoevasive tumor microenvironment
Kailiang Qiao1, Qing-Lin Yang1,2, Tuo Li2,3,4
1Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Biorxiv : the Preprint Server for Biology
|November 26, 2025
Summary
Extrachromosomal DNA (ecDNA) drives pancreatic cancer aggression and immune evasion by creating "super-expressor" cells. These cells remodel the tumor microenvironment, reducing T cell infiltration and promoting cancer growth.
Area of Science:
- Oncology
- Cancer Genetics
- Immunology
Background:
- Extrachromosomal DNA (ecDNA) contributes to cancer genetic heterogeneity.
- Emerging evidence suggests a link between ecDNA and immune evasion, but the underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role of ecDNA in pancreatic ductal adenocarcinoma (PDAC) progression and immune evasion.
- To elucidate the mechanism by which ecDNA influences the tumor microenvironment (TME) and anti-tumor immunity.
Main Methods:
- Genetically engineered mouse models of PDAC.
- Single-cell transcriptomic and histological analyses.
- Analysis of TME components, including cancer-associated fibroblasts (CAFs) and T cells.
Main Results:
- ecDNA-driven tumors, characterized by amplified Kras and Myc oncogenes, exhibit increased aggressiveness in immunocompetent mice.
- ecDNA promotes rapid establishment of an immunoevasive TME with increased myofibroblastic CAFs (myCAFs) and reduced T cell infiltration.
- A subset of cancer cells, termed "super-expressors," exhibit extremely high Kras expression, secrete amphiregulin, promote myCAF expansion, and suppress T cell infiltration.
Conclusions:
- ecDNA plays a causal role in remodeling the TME, contributing to pancreatic cancer heterogeneity and immune evasion.
- Super-expressor cells driven by ecDNA establish an immunoevasive niche in PDAC.
- Targeting ecDNA or its downstream effectors may represent a novel therapeutic strategy for PDAC.
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