Abstract B021: Claudin-1 expression promotes chemoresistance and cancer stem cell characteristics in colorectal cancer


 Background: Claudins are integral components of tight junction complexes. Beyond just passive cell adhesion molecules, they influence structural dynamics, molecular trafficking, and important cell signaling pathways. Claudins are often dysregulated in cancer, leading to changes in adhesion and metastatic potential. Claudin-1 (Cldn1) is expressed at low levels in normal colon but is highly expressed in colorectal cancer (CRC) and promotes epithelial-mesenchymal transition and metastasis. Cancer stem cells (CSCs) are a small subset of cancer cells that display increased capacity for self-renewal and can undergo symmetric and asymmetric division to reform tumors after treatment. CSCs are resistant to cytotoxic drugs and are thought to be responsible for treatment failure, metastasis, and relapse. Significance of problem: CRC is the second leading cause of cancer-related deaths in the United States with an estimated 151,030 new cases in 2022. Although CRC has an overall relative 5-year survival rate of 64%, prognosis varies dramatically with the stage at diagnosis. Localized CRC can be treated surgically and has a 5-year survival rate of 91%, while the survival rate of metastatic CRC falls to 15%. The primary problem in treating metastatic CRC is a combination of intrinsic and acquired chemoresistance. Therefore, understanding the mechanisms of chemoresistance is vital to developing effective therapies. Hypothesis: Claudin-1 expression in colorectal cancer increases resistance to chemotherapeutic drugs and promotes cancer stem cell characteristics. Experimental design: Bioinformatic analysis was performed on a database of responders and non-responders to standard-of-care CRC chemotherapy. Cldn1 expression was manipulated in CRC cell lines, and assays were performed to evaluate chemoresistance and CSC characteristics. Results: Bioinformatic analysis of a patient dataset of responders and non-responders to chemotherapy revealed that Cldn1 expression was positively correlated with resistance to FOLFOX treatment. It was also significantly correlated with colorectal CSC marker expression including CD44, CD133, and Lgr5. Overexpression of Cldn1 in SW480 cells led to a significant increase in resistance to 5-FU, side population and ALDH-high percentage, colorectal CSC markers, and tumorigenic potential, while knockout of Cldn1 in SW620 and DLD-1 cells led to a decreased response in these assays. Follow-up experiments identified the PDZ-binding domain of Cldn1 as essential for the chemoresistant phenotype. Specifically, both CD44 and its downstream target phospho-AKT are increased with the expression of full-length but not mutated Cldn1. Conclusion: Cldn1 expression induces chemoresistance and cancer stem cell properties in colorectal cancer. Because of this, Cldn1 may serve as a biomarker in CRC for prescribing more aggressive adjuvant therapy or as a molecule for targeted treatment aimed at the resistant tumor cells responsible for treatment failure and recurrence.
 Citation Format: Mark Primeaux, Saiprasad Gowrikumar, Dhundy Bastola, Punita Dhawan, Amar Singh. Claudin-1 expression promotes chemoresistance and cancer stem cell characteristics in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B021.