Abstract 2465: YKL-40 overexpression enhances metastatic potential and is a novel prognostic candidate and predictive biomarker for patients with colorectal cancer

Abstract Purpose: Although early detection and high-quality treatment options, metastatic colorectal cancer (mCRC) is the main cause of CRC-related mortality. Dissecting the mechanisms underlying CRC progression may identify new accurate markers for invasive tumors, which can also be used as druggable targets, providing further improvement in the patients clinical outcomes. YKL-40 is a glycosyl hydrolase functionally linked to increased proliferation, angiogenesis, migration, and invasion of tumor cells. Because in colorectal cancer (CRC), YKL-40 serological level may serve as a risk predictor and prognostic biomarker, we investigated the underlying mechanisms by which it may contribute to tumor progression and the clinical significance of its tissue expression in metastatic CRC. Experimental Design: HCT116 and Caco2 cells genetically engineered to achieve YKL-40 silencing/overexpression were used for cell motility, invasion and proliferation assays, and to measure EMT markers. The YKL-40 expression level was assessed in the early and late tumor phases obtained in the AOM/DSS mouse model, as well as in tumors and sera from CRC patients. Six independent cohorts of CRC patients were stratified by YKL-40 tissue expression to define its prognostic role and its effect on cetuximab and oxaliplatin treatment response. Results: YKL-40 high-expressing HCT116 and Caco2 cells showed increased motility, invasion and proliferation. YKL-40 up-regulation was associated with EMT signaling activation. In murine and human samples, elevated YKL-40 levels correlated with high-grade tumors. In retrospective analyses, YKL-40 elevated expression correlated with shorter survival in patients with advanced CRC. Strikingly, YKL-40 high tissue levels showed a predictive value for better response to cetuximab, even in patients with stage IV CRC and mutant KRAS, and worse sensitivity to oxaliplatin. Conclusions: Our study recognizes a novel role of YKL-40 tissue expression in promoting CRC metastatic potential, through EMT signaling activation, and provides significant clinical implications that may impact the risk prediction of patients with mCRC. YKL-40 high tissue levels also strengthen a predictive value for better cetuximab responsiveness, even in patients with KRAS mutations. Since resistance to cetuximab remains one of the greatest challenges in treating CRC, our findings may be crucial for developing novel YKL-40-targeted therapy approaches. Citation Format: Mariangela De Robertis, Maria Raffaella Greco, Rosa Angela Cardone, Tommaso Mazza, Flaviana Marzano, Nikolay Mehterov, Maria Kazakova, Nikolay Belev, Apollonia Tullo, Graziano Pesole, Victoria Sarafian, Emanuela Signori. YKL-40 overexpression enhances metastatic potential and is a novel prognostic candidate and predictive biomarker for patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2465.