The discovery of clinically useful targets to treat specific pathological conditions can provide novel therapeutic approaches. To unbiasedly identify key genes related to tumor metastasis, we developed a random gene perturbation method using a piggyBac transposon system under the control of a doxycycline regulated promoter. Using this random gene perturbation method and utilizing a mouse model of metastatic pancreatic cancer, we identified genes dysregulated in metastasized cells from a random mutagenesis library after multiple rounds of in vivo selection. Analysis of these metastasized clones revealed the downregulation of ARPC1B gene. Our further mechanistic studies revealed that ARPC1B gene and its closely related gene ARPC1A worked in a regulatory loop to control tumor metastasis. These findings validate that piggyBac transposon mediated random gene perturbation is a powerful tool to investigate the functional relevance of novel genes and the ARPC1A/B axis is a potential key regulator of tumor metastasis.