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The High-Intensity Focused Ultrasound combined with IL-2 to activate the JAK-STAT signaling pathway for treating breast cancer

ABSTRACT: In our study, we applied thermal High-Intensity Focused Ultrasound (HIFU) and mechanical HIFU for the treatment of breast cancer in murine models. This approach led to a notable increase in IL2RB expression among CD8+ T cells within the tumor microenvironment, suggesting a potential immunomodulatory effect. Further investigation revealed that this upregulation was associated with the activation of the JAK-STAT signaling pathway, a key mediator of immune responses. Building on these findings, we then explored the synergistic potential of combining IL-2 with HIFU. Our results indicated that this combined therapeutic strategy yielded significantly enhanced tumor regression in mouse models of breast cancer, outperforming the effects observed with either modality alone. This suggests that the integration of HIFU with IL-2 may offer a promising avenue for improving breast cancer treatment outcomes.

ORGANISM(S): Mus Musculus

SUBMITTER: Jiangbei Yuan

PROVIDER: PXD057039 | iProX | Tue Oct 22 00:00:00 BST 2024

REPOSITORIES: iProX

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Project description:Notch signaling is frequently hyperactivated in breast cancer, but how the enhanced signaling contributes to the tumor process is less well understood. In this report, we identify the proinflammatory cytokine interleukin-6 (IL-6) as a novel Notch target in breast tumor cells. Enhanced Notch signaling upregulated IL-6 expression at the transcriptional level, leading to activation of autocrine and paracrine JAK/STAT signaling. IL-6 upregulation was mediated by non-canonical Notch signaling, as it could be effectuated by a cytoplasmically localized Notch intracellular domain and was independent on the DNA-binding protein CSL. Instead, Notch-mediated IL-6 upregulation was controlled by two other factors: IKKÎ², a protein in the NF-kB signaling cascade, and p53. Activation of IL-6 by Notch required IKKÎ² function, but interestingly, did not engage canonical NF-ÎºB signaling, in contrast to IL-6 activation by inflammatory agents such as tumor necrosis factor, which requires canonical NF-ÎºB signaling. With regard to p53 status, IL-6 expression was upregulated by Notch when p53 was mutated or lost, but restoring wildtype 53 into p53-mutated or -deficient cells abrogated the IL-6 upregulation. Furthermore, Notch-induced genome-wide transcriptomes from p53 wildtype and -mutated breast tumor cell lines differed extensively, and in a subset of genes upregulated by Notch in a p53-mutant cell line, upregulation was reduced by wildtype p53. In conclusion, we identify IL-6 as a novel non-canonical Notch target gene, and reveal roles for p53 and IKKÎ² in non-canonical Notch signaling in breast cancer and in the generation of cell context-dependent diversity in the Notch signaling output. 30 microarray samples consisting of MCF7 (ER+, wild-type p53, luminal type B breast cancer) and MDA-MB-231 (ER-, mutated p53, basal breast cancer) cells cultured on immobilized 1 Î¼g/ml JAGGED1-Fc or 1 Î¼g/ml DLL4-Fc or 1 Î¼g/ml Fc control with or without 5 Î¼M DAPT for 6 hours in 3 biological replicates.

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The High-Intensity Focused Ultrasound combined with IL-2 to activate the JAK-STAT signaling pathway for treating breast cancer

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