ArticleNature cancer2025
SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence.
Article in Nature cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Itaconate and its derivatives in human health and diseases.Signal transduction and targeted therapy · 2026Review
- Rewiring metabolic-immune circuitry in pancreatic ductal adenocarcinoma (PDAC).Cancer pathogenesis and therapy · 2026Article
- Inactivation of CDKN2AARF Promotes p53-Independent Remodeling of the PDAC Tumor Microenvironment.Cancer research · 2026Article
- SMAD4 Palmitoylation Drives a Metabolic-Transcriptional Circuit to Promote Tumorigenesis and Confers Radiosensitivity in Pancreatic Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SIRT6 cooperates with KDM5C to transcriptionally silence MICAL2 and inhibit tumorigenesis in pancreatic cancer.Cell communication and signaling : CCS · 2026Article
- CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1.Molecular cancer · 2026Article
- Case Report: Pancreatic amphicrine-like carcinoma with acinar differentiation harboring a KANK4-RAF1 gene fusion.Pathology oncology research : POR · 2026Article
- Primary tumor chromatin landscape governs metastatic organotropism.Nature cancer · 2025Article
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Authors and funding
23 authors.
Funding
Abstract
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.
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