Metastatic site influences driver gene function in pancreatic cancer

Abstract

ABSTRACTDriver gene mutations can increase the metastatic potential of the primary tumor1–3, but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation ofSMAD4– a transcriptional effector of TGFβ signaling – which is a hallmark of multiple gastrointestinal malignancies4,5.SMAD4inactivation mediates TGFβ’s remarkable anti-to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis6–14. To determine whether metastatic tumors remain dependent onSMAD4inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enablesSmad4depletion in the pre-malignant pancreas and subsequentSmad4reactivation in established metastases. As expected,Smad4inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast,Smad4reactivation in metastatic disease had strikingly opposite effects depending on the tumor’s organ of residence: suppression of liver metastases and promotion of lung metastases. Integrative multiomic analysis revealed organ-specific differences in the tumor cells’ epigenomic state, whereby the liver and lungs harbored chromatin programs respectively dominated by the KLF and RUNX developmental transcription factors, withKlf4depletion being sufficient to reverseSmad4’s tumor-suppressive activity in liver metastases. Our results show how epigenetic states favored by the organ of residence can influence the function of driver genes in metastatic tumors. This organ-specific gene–chromatin interplay invites consideration of anatomical site in the interpretation of tumor genetics, with implications for the therapeutic targeting of metastatic disease.