SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence
The role of driver gene mutations in sustaining tumor growth at metastatic sites is poorly understood. SMAD4 inactivation is a paradigm of such mutations and a hallmark of pancreatic ductal adenocarcinoma (PDAC). To determine whether metastatic tumors are dependent on SMAD4 inactivation, we developed a mouse model of PDAC that enables spatiotemporal control of Smad4 expression. While Smad4 inactivation in the premalignant pancreas facilitated the formation of primary tumors, Smad4 reactivation in metastatic disease suppressed liver metastases but promoted lung metastases. These divergent effects were underpinned by organ-biased differences in the tumor cells' chromatin state that emerged in the premalignant pancreas and were distinguished by the dominance of KLF4 versus RUNX1 transcription factors. Our results show how epigenetic states favored by the organ of residence can influence the output of driver mutations in metastatic tumors, which has implications for interpreting tumor genetics and therapeutically targeting metastatic disease.
Authors
- Timour Baslan (ORCID: https://orcid.org/0000-0001-5674-6432)
- Jin Myung Park (ORCID: https://orcid.org/0009-0008-5266-5289)
- Direna Alonso‐Curbelo (ORCID: https://orcid.org/0000-0001-6674-3059)
- Nevenka Dimitrova (ORCID: https://orcid.org/0000-0003-4091-9233)
- Alexandra Wuest (ORCID: https://orcid.org/0000-0001-7337-8619)
- Scott W. Lowe (ORCID: https://orcid.org/0000-0002-5284-9650)
- John Erby Wilkinson (ORCID: https://orcid.org/0000-0001-9174-8556)
- Sha Tian (ORCID: https://orcid.org/0000-0002-5614-8480)
- Kaloyan M. Tsanov (ORCID: https://orcid.org/0000-0001-9007-4844)
- Ignas Masilionis (ORCID: https://orcid.org/0000-0001-7937-9014)
- Jordana Ray-Kirton
- Francisco M. Barriga (ORCID: https://orcid.org/0000-0002-0996-7707)
- Christine A. Iacobuzio–Donahue (ORCID: https://orcid.org/0000-0002-4672-3023)
- Wei Luan (ORCID: https://orcid.org/0000-0002-9988-0612)
- Joan Massagué (ORCID: https://orcid.org/0000-0001-9324-8408)
- Yu-Jui Ho (ORCID: https://orcid.org/0000-0002-7540-024X)
- Richard P. Koche (ORCID: https://orcid.org/0000-0002-6820-5083)
- Dana Pe’er (ORCID: https://orcid.org/0000-0002-9259-8817)
- Ronan Chaligné (ORCID: https://orcid.org/0000-0003-4332-3291)
- Janelle Simon
- Geulah Livshits (ORCID: https://orcid.org/0000-0002-3835-7377)
- Umesh Bhanot (ORCID: https://orcid.org/0000-0001-6656-1239)
- José Reyes (ORCID: https://orcid.org/0000-0002-1133-4933)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- University of Michigan (US)
- Kettering University (US)
- University of Chicago (US)
- May Institute (US)
- Institute for Research in Biomedicine (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Vall d'Hebron Institute of Oncology (ES)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1038/s43018-025-01047-5
- Citations
- 3
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 3.14