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<p>The role of driver gene mutations in sustaining tumor growth at metastatic sites is poorly understood. <i>SMAD4</i> inactivation is a paradigm of such mutations and a hallmark of pancreatic ductal adenocarcinoma (PDAC). To determine whether metastatic tumors are dependent on <i>SMAD4</i> inactivation, we developed a mouse model of PDAC that enables spatiotemporal control of <i>Smad4</i> expression. While <i>Smad4</i> inactivation in the premalignant pancreas facilitated the formation of primary tumors, <i>Smad4</i> 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.</p>

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SMAD4 induces opposite effects on metastatic growth from pancreatic tumors depending on the organ of residence

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Kaloyan M. Tsanov,
  • Francisco M. Barriga,
  • Yu-Jui Ho,
  • Direna Alonso-Curbelo,
  • Geulah Livshits,
  • Sha Tian,
  • Richard P. Koche,
  • Timour Baslan,
  • Janelle Simon,
  • Alexandra N. Wuest,
  • José Reyes,
  • Jin Park,
  • Wei Luan,
  • John E. Wilkinson,
  • Umesh Bhanot,
  • Jordana Ray-Kirton,
  • Ignas Masilionis,
  • Nevenka Dimitrova,
  • Christine A. Iacobuzio-Donahue,
  • Ronan Chaligné,
  • Dana Pe’er,
  • Joan Massagué,
  • Scott W. Lowe

摘要

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.