Here, we report a direct in vivo CRISPR/Cas9 screening strategy to identify which long-tail PDAC genes and associated pathways cooperate with oncogenic KrasG12D to accelerate pancreatic cancer progression and identify USP15 or SCAF1 as pancreatic tumor suppressors that regulate inflammatory responses and sensitivity to PARP inhibition and Gemcitabine. Here, USP15 is linked to familial pancreatic carcinoma.