Circulating cellular communication network factor 1 (CCN1) as a liquid biopsy marker indicating progression in advanced melanoma

BACKGROUND: Cellular communication network factor 1 (CCN1, also referred to as CYR61), a secreted matricellular protein, has been implicated in tumor progression and stromal remodeling within the metastatic tumor microenvironment of melanoma. Here, we investigated, for the first time, whether CCN1 circulating in the blood can serve as a biomarker in melanoma patients. METHODS: In this retrospective study, serum CCN1 levels before treatment initiation were measured by enzyme-linked immunosorbent assay (ELISA) in 95 patients with advanced melanoma (unresectable AJCC stage III and AJCC IV) treated with immune checkpoint inhibitors. The association between CCN1 serum levels and clinico-pathological parameters, as well as clinical outcomes, was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Moreover, CCN1 levels were also evaluated in relation to established biomarkers, including S100B. RESULTS: An optimal cutoff of 221.76 pg/mL was calculated for serum CCN1 to stratify patients into high and low CCN1 groups. No significant associations, despite T status, with demographic, clinico-pathological, or laboratory parameters of the CCN1 groups were detected. High serum CCN1 levels were significantly associated with reduced OS (median OS: 15 months vs. median OS not reached, p = 0.011), but only a trend was toward impaired PFS was detected. Combination of CCN1 with established prognosticators in melanoma, such as S100B serum levels, enhances risk stratification. Patients with high serum levels of both CCN1 and S100B exhibited the poorest prognosis (median OS: 5 months), while those with low levels of CCN1 and S100B had the most favorable outcomes (median OS not reached; overall log-rank p < 0.0001, adjusted p = 0.00032), indicating the complementary value of CCN1. In the multivariate Cox-regression analysis, CCN1 sustained as an independent prognostic factor of impaired OS (HR = 3.50, 95% CI: 1.69–7.26, p = 0.001) besides Eastern Cooperative Oncology Group (ECOG) performance status 2 (HR: 4.10, 95% CI 1.62–10.36, p = 0.003) and elevated S100B (HR: 4.64, 95% CI: 1.93–11.16, p = 0.001). CONCLUSION: CCN1 is an independent prognostic blood-based liquid biopsy biomarker for OS in advanced melanoma (especially if combined with S100B), suggesting a potential role in melanoma aggressiveness and potential involvement in immunotherapy resistance that warrants further functional investigation.