Genomic evolution of pancreatic cancer at single-cell resolution
Most evolutionary studies on pancreatic cancer rely on bulk sequencing, yet clonal evolution happens at the single-cell level. We used single-nucleus DNA sequencing to study 137,491 single nuclei from 24 pancreatic neoplasms reflecting various clinical scenarios. We found higher frequencies of somatic alterations to driver genes that bulk studies indicate; many manifest as copy number alterations and account for the majority of spatial heterogeneity. In pancreatic cancers with canonical KRAS oncogenic mutations, we found likely varied dependence on the genotype that may signify differential response to KRAS inhibition. In pancreatic cancers with germline heterozygous BRCA2 mutations, we discovered varied mechanisms and timing of inactivation of the wild-type allele that sculpted differential evolutionary trajectories. Inactivation of tumor-intrinsic response to transforming growth factor-β happens through various mechanisms, takes place after oncogenesis and coincides with invasion and metastasis, reflecting increasing selective pressure for the phenotype later in pancreatic ductal adenocarcinoma development.
Authors
- W. Park
- Anne Marie Noronha (ORCID: https://orcid.org/0000-0002-9066-8623)
- Palash Sashittal (ORCID: https://orcid.org/0000-0001-6581-4839)
- Akimasa Hayashi (ORCID: https://orcid.org/0000-0002-7424-8127)
- Akhil Jakatdar (ORCID: https://orcid.org/0000-0003-1580-010X)
- Nicolas LeComte
- Marc Hilmi (ORCID: https://orcid.org/0000-0003-4762-6740)
- Amanda Erakky
- Nan Pang (ORCID: https://orcid.org/0000-0002-9557-9451)
- Agustin Cardenas
- Christine A. Iacobuzio-Donahue
- Benjamin J. Raphael
- Haochen Zhang
- Jungeui Hong
- Caitlin A. McIntyre
- Alice C. Wei
- Shigeaki Umeda
- Elias-Ramzey Karnoub
Institutions
- Rutgers, The State University of New Jersey (US)
- Brigham and Women's Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- Kyorin University (JP)
- Princeton University (US)
- Cornell University (US)
- Johnson University (US)
- Weill Cornell Medicine (US)
- Institut Curie (FR)
- Virginia Tech (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2026-01-22
- DOI
- https://doi.org/10.1038/s41588-025-02468-9
- Citations
- 1
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 24.20
Funders
- Princeton University
- Cycle for Survival
- Daiichi-Sankyo
- Ligue Contre le Cancer
- Fondation de France
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Servier
- Institut Servier
- National Institutes of Health
- Stand Up To Cancer
- National Cancer Institute