Tasquinimod

Breast cancer is the most commonly diagnosed cancer in women globally. Our previous MIRACLE trial (NCT02313051) demonstrated that everolimus plus letrozole (E + L) significantly improves progression-free survival compared with letrozole (L) monotherapy in premenopausal patients with endocrine therapy-resistant, hormone receptor-positive, HER2-non-amplified advanced breast cancer. This study aims to investigate spatially resolved biomarkers linked to survival benefits from E + L to guide precision therapies. Patients from MIRACLE were stratified by overall survival (OS ≤ 3 vs. >3 years). Spatial Whole Transcriptome Atlas analysis was used to evaluate tumor-, immune-, and stroma-specific gene expression, co-expression network patterns, and survival correlations. Among patients with shorter survival (OS ≤ 3 years), we identified a distinctive gene interaction network characterized by tumor-derived S100A9 and CALML5, which is associated with mTORC1 activation. This finding suggests that tasquinimod, an S100A9 inhibitor, could be a viable therapeutic option. Additionally, an interaction between CALML5 and SLPI across tumor and immune areas indicated a potential role in maintaining tumor integrity and mitigating immune-mediated damage. Conversely, patients with longer survival (OS > 3 years) exhibited SERPINA1 as a hub gene linked to estrogen receptor activation, and an interaction between FKBP5 and SESN3 associated with AKT/mTORC1 inhibition within tumor-rich regions. Furthermore, the interaction between MMP11 and COL16A1 in stroma-rich regions suggests that cancer-associated fibroblasts may contribute to improved outcomes. Our study underscores the critical role of spatial gene expression analysis in elucidating the tumor microenvironment and its impact on prognosis in patients undergoing E + L treatment, thereby opening new avenues for targeted interventions.

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis(E. multilocularis) infection, is a severe parasitic disease characterized by progressive liver fibrosis. Although the damage-associated molecular pattern molecule S100A9 has been implicated in some inflammatory and fibrotic diseases, its role in AE induced liver fibrosis remains unclear. This study aimed to elucidate the function and mechanism of S100A9 in E. multilocularis induced liver fibrogenesis. Using proteomic analysis, we identified significant up-regulation of S100A9 in the livers of infected mice. In a stem cell-based fibrosis regression model, S100A9 expression correlated closely with the extent of fibrosis. Cellular localization and macrophage depletion experiments revealed macrophages as the primary source of S100A9. In vitro, recombinant S100A9 directly activated human hepatic stellate cells (HSCs) LX-2, up-regulating fibrotic markers in a time-dependent manner. Proteomic and molecular analyses further identified SPARC as a critical downstream mediator, and SPARC knockdown attenuated S100A9 induced HSCs activation and TGF-β/SMAD signaling. In vivo, pharmacological inhibition of S100A9 with tasquinimod significantly ameliorated liver fibrosis, down-regulated SPARC expression, and suppressed SMAD2/3 phosphorylation. Critically, histopathological analysis of liver tissues from AE patients confirmed that S100A9 expression was predominantly localized to fibrotic areas and positively correlated with fibrosis severity. Collectively, these results demonstrate that macrophage-derived S100A9 promotes HSCs activation and liver fibrosis via SPARC dependent way, mechanism, and its clinical relevance in human AE substantiates the S100A9-SPARC axis as a potential therapeutic target in AE.