Abstract 940: Loss of Pkd1 limits colorectal cancer by increasing colon barrier function
Authors: Nikonova Anna S. , Deneka Alexander Y. , Silva Flaviane , Tricarico Rosella , Kiseleva Anna , Grivennikov Sergey , Golemis Erica A. 
Published: June 2022

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. CRC typically arises from mutations that inactivate the tumor suppressor APC, which activates the WNT/CTNNB1 pathway to drive cell transformation and tumor growth. Identifying factors that reduce incidence of CRC is of high interest. Intriguingly, a large population study has found a decreased incidence of CRC in patients with autosomal dominant polycystic kidney disease (ADPKD), an inherited disease affecting approximately 1 in 1,000 individuals. ADPKD typically arises from germline mutations in the PKD1 gene, which encodes a transmembrane signaling protein that is ubiquitously expressed. Puzzlingly, activated WNT/CTNNB1 signaling is also found in ADPKD, which would be expected to enhance rather than reduce likelihood of CRC.

To investigate the role of PKD1 in modulating CRC tumorigenesis, we established a mouse model with tamoxifen-inducible loss of Apc with or without parallel loss of Pkd1 in the colon. Pkd1 loss vey significantly reduced tumor incidence (~80%) and rate of growth. In addition, growth of Pkd1-/-;Apc-/- organoids was reduced relative to Apc-/-organoids, indicating a cancer cell-intrinsic activity. Analysis of signaling pathway activation by RNA-seq indicated that Pkd1-deficient CRC organoids had enhanced WNT/CTNNB1 signaling, excluding reduced activation of this core driver pathway as a mechanism of action.

Considering alternative mechanisms, a prominent feature of ADPKD is reprogramming barrier function in renal cells to reduce permeability, supporting cyst development; notably, compromised integrity of the epithelial barrier is associated with CRC. We tested the hypothesis that loss of Pkd1 increased colon barrier integrity. As a first approach, we compared susceptibility of wt versus Pkd1-/- mice to dextran-sodium sulfate (DSS), which induces colitis by damaging epithelial barriers. Histopathological assessment confirmed significantly less DSS-induced damage of colon tissue in Pkd1-/- mice. Further, treatment of DSS-treated mice with orally gavaged FITC-dextran led to elevated FITC-dextran in the serum of wt versus Pkd1-/- mice, indicating greater passage through a functionally impaired barrier. In ADPKD, decreased barrier permeability is mediated by upregulation of specific claudins (CLDN4, 7); in CRC, these claudins are typically reduced during and promote tumor formation. We detected strong elevation of CLDN4 and CLDN7 in the colonic epithelium of Pkd1-/- versus wt mice, with the expressed proteins having consistently greater localization to cell junctions. Based on these and other data, we identify PKD1 control of barrier function as an important regulatory mechanism in CRC tumorigenesis, which may suggest novel therapeutic strategies based on targeting PKD1-associated effector pathways.

Citation Format: Anna S. Nikonova, Alexander Y. Deneka, Flaviane Silva, Rosella Tricarico, Anna Kiseleva, Sergey Grivennikov, Erica A. Golemis. Loss of Pkd1 limits colorectal cancer by increasing colon barrier function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 940.