Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer
Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes.
Authors
- Allison Creason (ORCID: https://orcid.org/0000-0001-5724-1276)
- Alex Guimaraes
- Gordon Brent Mills (ORCID: https://orcid.org/0000-0002-0144-9614)
- Elmar Bucher (ORCID: https://orcid.org/0000-0002-2929-2460)
- Terry K. Morgan (ORCID: https://orcid.org/0000-0003-0742-5012)
- Motoyuki Tsuda (ORCID: https://orcid.org/0000-0003-2873-1449)
- Michael W. Munks (ORCID: https://orcid.org/0000-0002-0335-7238)
- Michael B. Heskett (ORCID: https://orcid.org/0000-0003-2089-3910)
- Lisa M. Coussens (ORCID: https://orcid.org/0000-0003-2389-1865)
- Adel Kardosh (ORCID: https://orcid.org/0000-0002-6241-4896)
- Patrick J. Worth (ORCID: https://orcid.org/0000-0001-9600-0678)
- Jason M. Link (ORCID: https://orcid.org/0000-0002-6892-0431)
- Jeremy Goecks (ORCID: https://orcid.org/0000-0002-4583-5226)
- Carl Pelz (ORCID: https://orcid.org/0000-0002-2235-880X)
- Gustavo Salgado‐Garza (ORCID: https://orcid.org/0000-0002-6696-4043)
- Koei Chin (ORCID: https://orcid.org/0000-0001-8061-7462)
- Hannah D. Holly (ORCID: https://orcid.org/0000-0003-2055-5372)
- Emek Demir (ORCID: https://orcid.org/0000-0002-3663-7113)
- Sara Protzek
- Andrew C. Adey (ORCID: https://orcid.org/0000-0001-7648-8717)
- Brett C. Sheppard (ORCID: https://orcid.org/0000-0002-2182-7547)
- Brian Brinkerhoff (ORCID: https://orcid.org/0000-0002-6266-7965)
- David Kilburn
- Kevin MacPherson‐Hawthorne (ORCID: https://orcid.org/0000-0002-2657-8762)
- Julian Egger (ORCID: https://orcid.org/0000-0001-8418-0069)
- Isabel A. English (ORCID: https://orcid.org/0000-0002-0566-9585)
- Konjit Betre (ORCID: https://orcid.org/0009-0000-3707-2508)
- Sydney Owen
- Jennifer Eng (ORCID: https://orcid.org/0000-0003-1499-8417)
- Nell Kirchberger (ORCID: https://orcid.org/0009-0003-7024-705X)
- Alison Grossblatt-Wait (ORCID: https://orcid.org/0000-0002-2838-2595)
- Jonathan R. Brody (ORCID: https://orcid.org/0000-0003-3680-3270)
- Rosalie C. Sears (ORCID: https://orcid.org/0000-0003-1558-2413)
- Dove Keith (ORCID: https://orcid.org/0000-0001-6104-3264)
- Shamilene Sivagnanam (ORCID: https://orcid.org/0000-0001-5966-1522)
- Ellen M. Langer (ORCID: https://orcid.org/0000-0003-0352-1859)
- Zhi Hu
- Charles D. Lopez (ORCID: https://orcid.org/0000-0002-0921-4932)
Institutions
- Oregon Health & Science University (US)
- OHSU Knight Cancer Institute
- Stanford University (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-01-09
- DOI
- https://doi.org/10.1038/s43018-024-00881-3
- Citations
- 24
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 25.09
Funders
- U.S. Department of Defense
- American Association for Cancer Research
- National Cancer Institute