We find that deletion of mir-17~92 impairs MEK/ERK signaling in PanIN lesions and this correlates with the presence of fewer PanINs, as well as their regression over time. In addition, we find that mir-17~92 miRNAs, in particular miR-19 family miRNAs, promote PDAC cell invasion by regulating the formation of extracellular matrix-degrading invadopodia rosettes. Together, these findings illustrate important roles for mir-17~92 miRNAs during multiple phases of PDAC development and progression.