SMAD4 and neoplasm: Thus, Klf4 and Runx1 depletions are sufficient to reverse and blunt Smad4 function in liver and lung metastases, respectively, which demonstrates that KLF4 facilitates Smad4’s tumor-suppressive activity in the liver and RUNX1 contributes to Smad4’s tumor-promoting activity in the lungs (Extended Data Fig. 10j).