Using mouse models, we here establish that loss of Pkd1 greatly reduces CRC incidence and tumor growth induced by loss of the tumor suppressor Apc. Growth of Pkd1−/−;Apc−/− organoids was reduced relative to Apc−/− organoids, indicating a cancer cell-intrinsic activity, even though Pkd1 loss enhanced activity of pro-oncogenic signaling pathways. This evidence concerns the gene PKD1 and colorectal carcinoma.