Abstract 633: Integrin αVβ3 activation by thyroid hormones triggers JAK/STAT oncogenic pathways that promote T cell lymphoma dissemination
Authors: Debernardi María M. , Revuelta María V. , Sterle Helena , Gonzalez Gonzalo , Souza Ingrid L M , Correa Alejandro , Cerchietti Leandro , Cremaschi Graciela , Cayrol Florencia 
Published: March 2024

T cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative disorders with poor prognosis. Aberrant activation of JAK/STAT pathway is associated with lymphoma dissemination in TCL patients. Although the FDA approved the use of inhibitors to target this pathway (Ruxolitinib), significant toxic effects have been reported and their use is limited. Thus making an excellent opportunity to study biological factors that regulate the activation of these pathways. In this sense, we recently showed that thyroid hormones (THs) acting through integrin αVβ3 induced TCL proliferation, which is reduced in vitro and in vivo in the presence of integrin αVβ3 pharmacological inhibitor. Our aim is to evaluate the impact of THs on JAK/STAT pathway activation and their implications on anti-lymphoma therapy. For the in vitro assays we used human and murine TCL cell lines. We used EL4 cells and c57bl/6 syngeneic mice for in vivo analysis. Proteomic profiles were evaluated by LC-MS-MS analysis. The GSE58445 database was used for in silico analysis. We found that THs induced STAT1, 3 and 5 phosphorylation in TCL cells and that the integrin αVβ3 inhibitor, Cilengitide (Cile) blunted these effects (p&lt;0.05). Interestingly, we found that high mRNA expression levels of integrin β3 significantly correlate with worse overall survival in a cohort of TCL patients (p&lt;0.05). Additionally, Ruxolitinib (Ruxo) diminished THs-induced STATs phosphorylation (p&lt;0.05). As Ruxo reported toxic effects we aim to study alternative therapies such as Bexarotene (Bex), a synthetic retinoid used for cutaneous LCT treatment. We found that Bex significantly reduced cell viability in vitro of all TCL subtypes analyzed and combination with Cile resulted in improved anti-lymphoma activity (p&lt;0.01). Also, Ruxo significantly decreased TCL cell viability but to a lesser extent than Bex+Cile (p&lt;0.05). We previously found that BexT4+Cile (T4+, thyroxine supplementation) significantly decreases the in vivo growth of TCL tumors. To understand the mechanisms under this effects we analyzed tumor proteomics profiles and metalloprotease activity after 12 days of treatment. We found that BexT4+Cile regulates proteomic profiles related not only to lymphoma progression (JAK/STAT and PI3K-Akt signaling) but also pathways that impact the tumor microenvironment (TNF and angiogenic factors secretion and Th1/Th2 T cell differentiation). Regarding metalloprotease activity, we found that BexT+Cile inhibited MMP2 and MMP9 activity (p&lt;0.05). Finally, we evaluated the dissemination of TCL in an in vivo model (by vain tail) and found that BexT4+Cile reduced EL4 cell implantation into the liver and kidneys (p&lt;0.05). These results described the mechanisms by which THs induce the activation of JAK/STAT oncogenic pathway and showed how the inhibition of integrin αvβ3 in combination with bexarotene has therapeutic potential for TCL.

Citation Format: María M. Debernardi, María V. Revuelta, Helena Sterle, Gonzalo Gonzalez, Ingrid L M Souza, Alejandro Correa, Leandro Cerchietti, Graciela Cremaschi, Florencia Cayrol. Integrin αVβ3 activation by thyroid hormones triggers JAK/STAT oncogenic pathways that promote T cell lymphoma dissemination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 633.