结直肠癌（CRC）是最常见的癌症之一，在美国每年约有13.5万例发病率，与5万名死亡有关。伴随PKD1基因失活突变的常染色体显性多囊肾病（ADPKD）可能影响1000人中的1人。有趣的是，一些研究已经提出，PKD1致病基因突变可能会降低结直肠癌的发病率，暗示可能存在一种基因修饰功能。通过小鼠模型，本研究证实了Pkd1缺失显著降低了Apc肿瘤抑制基因缺失引起的CRC发生率和肿瘤生长。相对于Apc缺失的有机样，Pkd1-/-;Apc-/-有机体的生长受到抑制，表明存在肿瘤细胞内固有的活性，尽管Pkd1缺失增强了促癌信号通路的活性。值得注意的是，Pkd1缺失增加了结肠屏障功能，Pkd1缺失动物耐受DSS诱导的结肠炎，与减少渗透性的克劳丁上调和T细胞浸润有关。值得注意的是，Pkd1缺失增加了CFTR的敏感性，该基因在CRC中起抑制肿瘤作用，与ADPKD中的信号关系相似。总的来说，这些数据和其他数据表明，PKD1的胚系突变和体细胞突变可能会影响人类CRC及其他涉及结肠的疾病的发病率、表现和治疗反应。© 2023. Springer Nature America, Inc.

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.© 2023. Springer Nature America, Inc.