Metastatic site influences driver gene function in pancreatic cancer

Driver gene mutations can increase the metastatic potential of the primary tumor[1][1]–[3][2], but their role in sustaining tumor growth at metastatic sites is poorly understood. A paradigm of such mutations is inactivation of SMAD4 – a transcriptional effector of TGFβ signaling – which is a hallmark of multiple gastrointestinal malignancies[4][3],[5][4]. SMAD4 inactivation mediates TGFβ’s remarkable anti-to pro-tumorigenic switch during cancer progression and can thus influence both tumor initiation and metastasis[6][5]–[14][6]. To determine whether metastatic tumors remain dependent on SMAD4 inactivation, we developed a mouse model of pancreatic ductal adenocarcinoma (PDAC) that enables Smad4 depletion in the pre-malignant pancreas and subsequent Smad4 reactivation in established metastases. As expected, Smad4 inactivation facilitated the formation of primary tumors that eventually colonized the liver and lungs. By contrast, Smad4 reactivation 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, with Klf4 depletion being sufficient to reverse Smad4 ’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. ### Competing Interest Statement S.W.L. is a consultant for Fate Therapeutics, and is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus, PMV Pharmaceuticals, Faeth Therapeutics, and Senescea Therapeutics. R.P.K. is a co-founder of and consultant for Econic Biosciences. D.P. is on the scientific advisory board of Insitro. J.M. holds equity in Scholar Rock. All other authors have no competing interests. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this report. [1]: #ref-1 [2]: #ref-3 [3]: #ref-4 [4]: #ref-5 [5]: #ref-6 [6]: #ref-14