Transcriptomic Plasticity is a Hallmark of Metastatic Pancreatic Cancer
Metastasis is the leading cause of cancer deaths. To develop strategies for intercepting metastatic progression, a better understanding of how tumor cells adapt to vastly different organ contexts is needed. To investigate this question, a single-cell transcriptomic atlas of primary tumor and diverse metastatic samples (liver, omentum, peritoneum, stomach wall, lymph node, and diaphragm) from a patient with pancreatic ductal adenocarcinoma who underwent rapid autopsy was generated. Using unsupervised archetype analysis, both shared and site-specific gene programs were identified, including lipid metabolism and gastrointestinal programs prevalent in peritoneal and stomach wall lesions, respectively. We developed PICASSO as a probabilistic approach for inferring clonal phylogeny from single-cell and matched whole-exome sequencing data. Comparison of PICASSO-generated clonal structure with phenotypic signatures revealed that pancreatic cancer cells adapted to local environments with minimal contribution from clonal genotype. Our results suggest a paradigm whereby strong environmental effects are imposed on highly plastic cancer cells during metastatic dissemination.
Authors
- Arnav Mehta (ORCID: https://orcid.org/0000-0002-0313-2848)
- Alejandro Jiménez-Sánchez (ORCID: https://orcid.org/0000-0003-1879-7057)
- Itsik Pe’er (ORCID: https://orcid.org/0000-0002-6128-7231)
- Feiyang Zhu (ORCID: https://orcid.org/0009-0007-7487-3348)
- Akimasa Hayashi (ORCID: https://orcid.org/0000-0002-7424-8127)
- Wungki Park (ORCID: https://orcid.org/0000-0002-8006-3102)
- Ignas Masilionis (ORCID: https://orcid.org/0000-0001-7937-9014)
- Yubin Xie (ORCID: https://orcid.org/0000-0003-2542-2544)
- Christine A. Iacobuzio–Donahue (ORCID: https://orcid.org/0000-0002-4672-3023)
- Tal Nawy (ORCID: https://orcid.org/0000-0003-3720-3699)
- Roshan Sharma (ORCID: https://orcid.org/0000-0001-9886-009X)
- Sitara Persad (ORCID: https://orcid.org/0009-0009-0422-3280)
- Linas Mažutis (ORCID: https://orcid.org/0000-0002-5552-6427)
- Dana Pe’er (ORCID: https://orcid.org/0000-0002-9259-8817)
- Eileen Mary O'Reilly (ORCID: https://orcid.org/0000-0002-8076-9199)
- Tinyi Chu (ORCID: https://orcid.org/0000-0003-3369-6692)
- Ronan Chaligné (ORCID: https://orcid.org/0000-0003-4332-3291)
- Jungeui Hong (ORCID: https://orcid.org/0009-0009-5998-2102)
- Shigeaki Umeda (ORCID: https://orcid.org/0000-0001-5693-1515)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Vilnius University (LT)
- Kyorin University (JP)
- Massachusetts General Hospital (US)
- University of Missouri (US)
- Columbia University (US)
Publication Details
- Journal
- Cancer Research
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1158/0008-5472.can-25-1117
- Citations
- 1
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 1.05