Integrin alphavbeta3-driven secretome remodeling uncovers THBS1 as a potential prognostic mediator in cutaneous T-cell lymphoma

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of T-cell non-Hodgkin lymphomas whose progression depends on dynamic interactions with the tumor microenvironment. Thyroid hormones (THs), at physiological concentrations, act through the membrane receptor integrin alphavbeta3 to activate oncogenic signaling such as MAPK and JAK/STAT, promoting proliferation and dissemination in T-cell lymphomas. However, the impact of this pathway on the CTCL secretome and its contribution to disease progression remain poorly characterized. Here, we analyzed how integrin alphavbeta3 activation modulates the CTCL secretome using Mycosis Fungoides (MJ) and Sézary Syndrome (HuT78) cell lines treated with THs (T4=100 nM, T3=1 nM) with or without the alphavbeta3 inhibitor cilengitide (1.5 μM). Proteins secreted into supernatants were analyzed by LC-MS/MS, and differential expression was evaluated using limma and ShinyGO. Under basal conditions, HuT78 secretome displayed a more aggressive profile, enriched in angiogenesis, metabolic reprogramming, and immune evasion pathways compared to MJ. TH treatment significantly altered the secretome composition in both models, with 66 proteins upregulated and 54 downregulated in HuT78 (FDR <0.1). Enriched pathways included VEGFA-VEGFR2, focal adhesion, and TGF-beta signaling, all of which are associated with tumor dissemination and immunosuppressive remodeling. THBS1, FN1, FLNA, FLNB, and TLN1 were among the top upregulated proteins and are functionally related to extracellular matrix organization, endothelial activation, and inhibition of antitumor immunity. Importantly, integrin alphavbeta3 blockade with cilengitide reversed the TH-induced upregulation of these proteins, demonstrating integrin dependence. Transcriptomic analysis of CTCL patient datasets (GSE113113, GSE168508) revealed that the expression of protein THBS1 positively correlates with ITGB3 (p<0.05) and is significantly increased in advanced disease stages, consistent with poorer survival. Together, our results show that physiological activation of integrin alphavbeta3 by THs reshapes the CTCL secretome toward a pro-tumorigenic and immunosuppressive state. THBS1 emerges as a potential prognostic mediator within this network, underscoring how systemic factors like hormones can influence lymphoma progression and revealing new molecular targets with diagnostic and therapeutic relevance.