Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of ~135,000 in the US, associated with ~50,000 deaths. Autosomal dominant polycystic kidney disease (ADPKD), associated with mutations disabling the PKD1 gene, affects as many as 1 in 1000. Intriguingly, some studies have suggested that individuals with germline mutations in PKD1 have reduced incidence of CRC, suggesting a genetic modifier function. 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. Notably, Pkd1 loss increased colon barrier function, with Pkd1-deficient animals resistant to DSS-induced colitis, associated with upregulation of claudins that decrease permeability, and reduced T cell infiltration. Notably, Pkd1 loss caused greater sensitivity to activation of CFTR, a tumor suppressor in CRC, paralleling signaling relations in ADPKD. Overall, these data and other data suggest germline and somatic mutations in PKD1 may influence incidence, presentation, and treatment response in human CRC and other pathologies involving the colon.

结直肠癌 (CRC) 是最常见的癌症之一，在美国每年发病率约为 135,000 例，导致约 50,000 例死亡。常染色体显性多囊肾病 (ADPKD) 与PKD1基因突变相关，影响多达千分之一。有趣的是，一些研究表明，PKD1种系突变的个体可降低 CRC 的发病率，这表明遗传修饰功能。使用小鼠模型，我们在此确定Pkd1的缺失大大降低了 CRC 的发病率以及肿瘤抑制因子Apc缺失引起的肿瘤生长。Pkd1 ^−/− ;Apc ^−/−类器官的生长相对于Apc ^−/−类器官有所减少，表明癌细胞固有的活性，尽管Pkd1损失增强了促癌信号通路的活性。值得注意的是，Pkd1 的丧失增强了结肠屏障功能，Pkd1缺陷的动物对 DSS 诱导的结肠炎具有抵抗力，这与降低通透性和减少 T 细胞浸润的密蛋白上调有关。值得注意的是，Pkd1丢失导致对 CFTR（CRC 中的肿瘤抑制因子）激活更加敏感，与 ADPKD 中的信号传导关系相似。总体而言，这些数据和其他数据表明PKD1的种系和体细胞突变可能会影响人类 CRC 和涉及结肠的其他病理的发病率、表现和治疗反应。