Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. One major reason for this is that PDAC quickly metastasizes to other organs, thereby making its treatment difficult. The molecular machinery driving PDAC metastasis is still poorly understood. In this study, we applied an unbiased approach using CRISPR screening to identify genes that strongly regulate invasion (based on an in vitro assessment of their metastatic potential) in PANC-1, a PDAC cell line. Through CRISPR screening, we identified MBNL3 and KANSL2 as strong regulators of invasion in PANC-1 cells. We further validated MBNL3 and KANSL2 as regulators of PANC-1 cell invasion by using the doxycycline-inducible shRNA system. We also showed that MBNL3 and KANSL2 do not affect cell proliferation. Through our efforts, we have established a process to identify genes that regulate cell invasion and can be further investigated as potential targets for therapeutic intervention.