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PubMed2025

CRISPR/Cas9 screenings reveal the role of STX1A and CDK1 in Cathepsin G entering and killing colorectal cancer cells.

Neutrophils are the major populations of white blood cells and have been reported to facilitate cancer metastasis. Meanwhile, emerging evidence has recently suggested the anti-cancer role of neutrophils. Our previous study revealed that CB-839 and 5-FU-treated colorectal cancer (CRC) tumors recruited neutrophils and induced neutrophil extracellular traps (NETs). Cathepsin G (CTSG), which is released during NET formation, enters CRC cells through the receptor for advanced glycation end products (RAGE) and cleaves 14-3-3ε to promote apoptosis. However, the detailed mechanism underlying CTSG's anti-tumor function remains less studied. In this study, we report that CTSG enters CRC cells through RAGE-mediated endocytosis. Knocking out RAGE or inhibiting endocytosis blocks CTSG from entering CRC cells and attenuates CTSG-induced apoptosis. Furthermore, the clathrin coat assembly complex and SNARE proteins were enriched in an arrayed CRISPR/Cas9 screening targeting human membrane trafficking genes. Knocking out SNARE protein STX1A prevents the spread of CTSG in CRC cells and the induction of cleaved PARP. A pooled genome-wide CRISPR/Cas9 screening further identifies the role of CDK1 in the NET-induced killing of CRC cells. Inhibiting CDK1 protected CRC cells from killing by CTSG. Our study reveals novel mechanisms by which CTSG enters and kills CRC cells.

CDK1↗
PubMed2026

CTSG Suppresses Breast Cancer Progression by Inhibiting the EGFR/ERK Signaling Pathway and Enhancing CD8⁺ T Cell Activation.

BACKGROUND: Breast cancer (BC), the most common female malignancy, has metastasis as its main cause of mortality. Cathepsin G (CTSG) is involved in tumorigenesis and immunity. This study explores the role of CTSG in BC progression and CD8 + T cell regulation. METHODS: Differentially expressed genes and proteins (DEGs/DEPs) were analyzed using Limma, and core genes were screened using Random Forest (RF) and Least absolute shrinkage and selection operator (LASSO). CTSG expression was analyzed using GSE36295, the Cancer Genome Atlas (TCGA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot. Cell viability, proliferation, cell cycle, migration, and invasion were detected using Cell Counting Kit-8 (CCK8), 5&#x2011;Ethynyl&#x2011;2'&#x2011;deoxyuridine (EdU), flow cytometry, and Transwell assays, respectively. Sphere diameter was analyzed via sphere formation assay. Downstream mechanisms were examined using western blot, CCK8, flow cytometry, and Transwell assays. CD8 + T cell activity was examined using EdU, western blot, and flow cytometry. RESULTS: A total of 177 genes overlapped between GSE36295 DEGs and PDC000173 DEPs. CTSG was the hub gene identified by RF and LASSO. CTSG expression was significantly reduced in BC (P < 0.01). CTSG overexpression suppressed cell viability, proliferation, migration, invasion, sphere formation, and CD44 and CD133 expression (P < 0.01). CTSG up-regulation inhibited epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) signaling axis and reduced cancer cell malignancy (P < 0.01). CTSG overexpression activated CD8 + T cells via EGFR/ERK inhibition, enhancing their cytotoxic effect on cancer cells (P < 0.01). CONCLUSION: CTSG inhibits BC malignancy and enhances CD8 + T cell function via EGFR/ERK inhibition.

Humans↗
PubMed2026

Construction of a new predictive model in head and neck squamous cell carcinoma based on the investigation of extracellular matrix-associated genes.

A key aspect influencing immune cell infiltration is the composition of the extracellular matrix (ECM). Therefore, investigating the association between ECM-associated proteins and immune cell infiltration is key for the identification of new biomarkers to distinguish 'immune-hot' solid tumors and predict patient prognosis. A total of 513 head and neck squamous cell carcinoma (HNSCC) cases as training samples from The Cancer Genome Atlas and an additional 270 as testing samples from the Gene Expression Omnibus were obtained for use in the present study. Using a single-sample Gene Set Enrichment Analysis method, the 513 training samples were divided into Cluster 1 and Cluster 2. Subsequently, the present analysis uncovered 1,573 differentially expressed genes distinguishing the two clusters. After performing an intersection analysis with 751 ECM-associated genes, 103 differentially expressed ECM-associated genes were identified. Least absolute shrinkage and selection operator-Cox and multivariate Cox regression analyses were employed to identify candidate ECM risk genes (P<0.05) and to construct a predictive model. Finally, a nomogram and a three gene (cerebellin 2, galectin-10 and cathepsin G) predictive model were developed. Therefore, the present prognostic risk score model can evaluate the immune infiltration, predict the prognosis of HNSCC, and potentially guide more personalized immunotherapy interventions.

extracellular matrix↗
PubMed2026

Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling.

Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 &#x3bc;m2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell-cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over &#x223c;200 &#x3bc;m distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.

Humans↗