Senescence as a dictator of patient outcomes and therapeutic efficacies in human gastric cancer

Senescence is believed to be a pivotal player in the onset and progression of tumors as well as cancer therapy. However, the guiding roles of senescence in clinical outcomes and therapy selection for patients with cancer remain obscure, largely due to the absence of a feasible senescence signature. Here, by integrative analysis of single cell and bulk transcriptome data from multiple datasets of gastric cancer patients, we uncovered senescence as a veiled tumor feature characterized by senescence gene signature enriched, unexpectedly, in the noncancerous cells, and further identified two distinct senescence-associated subtypes based on the unsupervised clustering. Patients with the senescence subtype had higher tumor mutation loads and better prognosis as compared with the aggressive subtype. By the machine learning, we constructed a scoring system termed as senescore based on six signature genes: ADH1B, IL1A, SERPINE1, SPARC, EZH2, and TNFAIP2. Higher senescore demonstrated robustly predictive capability for longer overall and recurrence-free survival in 2290 gastric cancer samples, which was independently validated by the multiplex staining analysis of gastric cancer samples on the tissue microarray. Remarkably, the senescore signature served as a reliable predictor of chemotherapeutic and immunotherapeutic efficacies, with high-senescore patients benefited from immunotherapy, while low-senescore patients were responsive to chemotherapy. Collectively, we report senescence as a heretofore unrecognized hallmark of gastric cancer that impacts patient outcomes and therapeutic efficacy.

Resveratrol Analog 4-Bromo-Resveratrol Inhibits Gastric Cancer Stemness through the SIRT3-c-Jun N-Terminal Kinase Signaling Pathway

Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4′-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell–targeted therapy.

miR-149 Suppresses the Proliferation and Metastasis of Human Gastric Cancer Cells by Targeting FOXC1

Purpose. Gastric cancer is one of the most common cancers in the world. miRNAs play an important role in regulating gene expression by binding with 3 ′ -UTR of the target gene. The aim of this study was to investigate the function of miRNA-149 and FOXC1 in gastric cancer. Patients and Methods. qRT-PCR was used to detect the expression of miRNA-149 and FOXC1 in gastric cancer tissues and cells. Human gastric cancer cell lines AGS and MKN28 were cultured and transfected with miR-149 overexpression plasmid and its control or FOXC1 siRNA and its control. The MTT, colony formation, flow cytometry, wound healing, transwell, and western blotting were performed to examine the function of miRNA-149 and FOXC1 in the development of gastric cancer. What is more, dual-luciferase assay and western blotting were used to demonstrated the relationship between miRNA-149 and FOXC1. Results. miRNA-149 was underexpressed in gastric cancer tissues and cells, while overexpression of miRNA-149 promoted cell apoptosis, retarded cell cycle, and inhibited proliferation and migration in AGS and MKN28 cells. In addition, we showed that miRNA-149 targeted FOXC1. What is more, FOXC1 was highly expressed in gastric cancer tissues and cells; the silencing of FOXC1 inhibited the biological function of AGS and MKN28 cells. Conclusion. miRNA-149 inhibits the biological behavior of gastric cancer by targeting FOXC1, providing a promising target in the treatment of human gastric cancer.

Disruption of Her2-Induced PD-L1 Inhibits Tumor Cell Immune Evasion in Patient-Derived Gastric Cancer Organoids

(1) Background: The expression of programmed death-ligand 1 (PD-L1), which interacts with programmed cell death protein 1 (PD-1) on cytotoxic T lymphocytes (CTLs), enables tumors to escape immunosurveillance. The PD-1/PD-L1 interaction results in the inhibition of CTL proliferation, and effector function, thus promoting tumor cell evasion from immunosurveillance and cancer persistence. Despite 40% of gastric cancer patients exhibiting PD-L1 expression, only a small subset of patients responds to immunotherapy. Human epidermal growth factor receptor2 (HER2) is one of the critical regulators of several solid tumors, including metastatic gastric cancer. Although half of PD-L1-positive gastric tumors co-express HER2, crosstalk between HER2 and PD-1/PD-L1 in gastric cancer remains undetermined. (2) Methods: Human gastric cancer organoids (huTGOs) were generated from biopsied or resected tissues and co-cultured with CTLs and myeloid-derived suppressor cells (MDSCs). Digital Spatial Profiling (DSP) was performed on FFPE tissue microarrays of numerous gastric cancer patients to examine the protein expression of immune markers. (3) Results: Knockdown of HER2 in PD-L1/HER2-positive huTGOs led to a concomitant decrease in PD-L1 expression. Similarly, in huTGOs/immune cell co-cultures, PD-L1 expression decreased in huTGOs and was correlated with an increase in CTL proliferation which enhanced huTGO death. Treatment with Nivolumab exhibited similar effects. However, a combinatorial treatment with Mubritinib and Nivolumab was unable to inhibit HER2 expression in co-cultures containing MDSCs. (4) Conclusions: Our study suggested that co-expression of HER2 and PD-L1 may contribute to tumor cell immune evasion. In addition, autologous organoid/immune cell co-cultures can be exploited to effectively screen responses to a combination of anti-HER2 and immunotherapy to tailor treatment for gastric cancer patients.