cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment

Abstract

Background Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. Methods Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. Results In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. Conclusions Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

“…Upon the completion of all cycles, the images are compiled and aligned to achieve a multiplex image [7]. This cycle-dependent approach drastically increased the number of potential markers, and opened opportunities for detailed characterization and spatial exploration of the TME [20,42].…”

“…More recently, PhenoCycler has also been used to elucidate the role of the S100A7/cytosolic phospholipase A2 (cPLA2)/Prostaglandin E2 (PGE2) signaling pathway in breast cancer; it was found that S100A7 is associated with tumor growth and metastasis [20]. Breast cancerbearing mice that overexpressed S100A7 were treated with the cPLA2 inhibitor, and the analysis revealed changes in T cell composition and cellular interactions.…”

Focal Adhesion Kinase (FAK)-Hippo/YAP transduction signaling mediates the stimulatory effects exerted by S100A8/A9-RAGE system in triple-negative breast cancer (TNBC)

“…RAGE is a multi-ligand pattern recognition receptor binding to several ligands such as advanced glycation end products (AGEs), high mobility group box-1 peptide (HMGB-1), amyloid-β peptides and the S100-Ca 2+ family proteins [ 86 , 87 ]. Upon stimulation, RAGE activates several oncogenic signaling pathways and gene expression programs which in turn promote pro-inflammatory responses and malignant progression [ 88 – 90 ]. Particularly, interfering with RAGE-ligand mediated signaling impairs cell viability, adhesion, migration and invasion of TNBC cells [ 17 , 91 – 93 ].…”

Machine Learning Assistants Construct Oxidative Stress-Related Gene Signature and Discover Potential Therapy Targets for Acute Myeloid Leukemia

“…It has been identified as an index in response to oxidative stress in preeclampsia and might be due to the oxidation of AA [ 27 ]. Higher expression of PLA2G4A is positively correlated with the migration and invasion of lung cancer cells and unfavorable prognosis in breast cancers [ 31 , 32 ]. Previous studies also revealed that PLA2G4A expression could be an independent diagnostic and prognostic marker in patients with non-M3/NPM1 WT AML patients [ 33 ], which was also confirmed in our study.…”