Tissue architecture and immune niches govern ctDNA release in colorectal cancer
Abstract Circulating tumor DNA (ctDNA) is central to liquid biopsy-based cancer detection, yet the biological basis of its highly variable release into the bloodstream remains poorly understood. To define the tissue-level determinants of ctDNA shedding in colorectal cancer (CRC), we integrated tumor-informed plasma sequencing with detailed histopathology, immunophenotyping, spatial transcriptomics, and in situ mutation detection in resectable stage I–III disease. ctDNA detectability increased with tumor burden, and ctDNA shedders exhibited a distinct architectural and microenvironmental phenotype characterized by expanded pseudolumina containing necrotic debris, frequent epithelial barrier disruption, and dense myeloid infiltration in lumina and stroma. Spatial profiling revealed stress-associated malignant programs and a myeloid-rich immune-luminal niche. In situ mutation detection localized plasma-identified mutations to necrotic material within pseudoluminal structures, establishing these compartments as focal reservoirs of shed DNA. These findings provide a mechanistic framework linking tissue architecture, immune remodelling, and spatially organized cell death to ctDNA release with implications for refining liquid biopsy applications.
Authors
- Mats F. Nilsson (ORCID: https://orcid.org/0000-0001-9985-0387)
- Rudolf Oehler (ORCID: https://orcid.org/0000-0003-2891-7155)
- Felix Aigner (ORCID: https://orcid.org/0000-0001-8931-736X)
- Lilli Bonstingl (ORCID: https://orcid.org/0009-0009-0757-6962)
- Katja Sallinger (ORCID: https://orcid.org/0000-0003-1130-2314)
- Maria Escriva Conde (ORCID: https://orcid.org/0009-0005-3891-8794)
- Stefan Uranitsch (ORCID: https://orcid.org/0000-0001-7338-4875)
- Jasmin Blatterer
- Stefan Kühberger (ORCID: https://orcid.org/0000-0002-9063-1732)
- Silvia Andaloro (ORCID: https://orcid.org/0009-0004-0734-9712)
- Sigurd Lax (ORCID: https://orcid.org/0000-0002-3576-601X)
- Ricarda Graf (ORCID: https://orcid.org/0000-0002-0209-7315)
- Ellen Heitzer (ORCID: https://orcid.org/0000-0002-8815-7859)
- Gerald Höefler (ORCID: https://orcid.org/0000-0002-9056-3063)
- Amin El‐Heliebi (ORCID: https://orcid.org/0000-0002-7679-6856)
- Christine Beichler
- Christin-Therese Müller
- Karin Pankratz
- Gabriele Moitzi
- Julia Enzi (ORCID: https://orcid.org/0009-0001-4095-4824)
- Karin Strohmeyer
- Hannes Schmölzer
- Hubert Hauser
- Sarah Binder
- Sergio Marco Salas
- Antonia Syrnioti
- Martina Scheiber
Institutions
- Stockholm University (SE)
- Medical University of Graz (AT)
- Science for Life Laboratory (SE)
- LKH Hochsteiermark (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2026-11-01
- DOI
- https://doi.org/10.1038/s41419-026-09315-7
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancerfonden
- Vetenskapsrådet
- Christian Doppler Forschungsgesellschaft
- Medizinische Universität Graz
- Bundesministerium für Digitalisierung und Wirtschaftsstandort