Journal article
Loss of Pkd1 limits susceptibility to colitis and colorectal cancer
ONCOGENESIS, v 12(1), 40
05 Aug 2023
PMID: 37542051
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Colorectal cancer (CRC) is one of the most common cancers, with an annual incidence of similar to 135,000 in the US, associated with similar to 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.
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Details
- Title
- Loss of Pkd1 limits susceptibility to colitis and colorectal cancer
- Publication Details
- ONCOGENESIS, v 12(1), 40
- Publisher
- SPRINGERNATURE; LONDON
- Grant note
- We are grateful for support from Dr. Margret Einarson of the Fox Chase Cancer Center (FCCC) High Throughput Screening facility, and Dr. Kathy Cai of the FCCC Histopathology Facility. We thank Drs. Ilya Serebriiskii and Kerry Campbell for helpful discussions and comments. We thank Ms. Anna Lilly for assistance with immunofluorescence analysis. We are grateful to Dr. Gregory Germino, NIDDK, for the gift of the floxed Pkd1 mice. The authors and study received support from NIH R01s DK108195 and CA228187, the William Wikoff Smith Charitable Trust and S10 OD021754 (to EAG); by NIH T32 CA009035 (to AN); by a William J. Avery Postdoctoral Fellowship from Fox Chase Cancer Center (to AD); by Marie Sklodowska-Curie grant No 896865 from the European Union's Horizon 2020 research and innovation program (to RT), NIH R01CA227629 and CA218133 (to SIG) and by the NCI Core Grant P30 CA006927 (to Fox Chase Cancer Center).
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:001042522900001
- Scopus ID
- 2-s2.0-85167438590
- Other Identifier
- 991021861284504721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology