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Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes for advanced gastric cancer with different ferroptosis-related-scores

ABSTRACT: Gastric cancer is one of the leading causes of cancer mortality worldwide. We compared transcriptomic profiles of gastric cancer with different ferroptosis-related-scores to identify the prognostic significance of ferroptosis-related-score in gastric cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184336 | GEO | 2021/11/29

REPOSITORIES: GEO

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Project description:Purpose: Gastric cancer remains one of the deadliest neoplasms worldwide, with a high need for new therapeutic options. Efficacies of targeted therapies are often limited owing to the inter- and intratumoral heterogeneity of gastric cancer. Thus, drugs with broader mechanisms of action rather than relying on the inhibition of a single specific oncogene are needed. Preclinical studies have identified histone deacetylases (HDAC) and their respective isoforms as potential therapeutic targets in gastric cancer. However, clinical efficacies are moderate and the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. Methods: In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured using flow cytometry. Proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA (RT-qPCR) and protein level (Western Blot). Results: Upon HDACi treatment, lipid peroxidation levels were found increased in all tested cell lines. Class-I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Alterations of POR and SLC7A11 levels upon treatment were also confirmed in primary human gastric cancer tissue cultures as relevant ex vivo model. Conclusion: We identify the induction of ferroptosis as a new mechanism of action of class-I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle besides other, less broadly usable targeted drugs.

Project description:Gastric adenocarcinoma (GAC) remains a significant cause of cancer-related deaths worldwide, with the majority of mortality resulting from metastatic spread. To elucidate the evolution of cancer cells and their interactions with the tumour microenvironment (TME), we conducted a comprehensive single-cell transcriptome and immune repertoire profiling of primary tumours (PRIs), matched liver metastases (LMs) or peritoneal carcinomatosis (PC), adjacent normal tissues, and blood samples from 20 treatment-naïve patients. We found that the TME within metastases varied substantially from PRIs and differed between LMs and PC samples. Indicative of immune evasion, we observed diminished T cell clonal expansion, a marked reduction in the fraction of tumour-reactive CD8 T cells, and an enrichment of naïve T cells, M2-like, and proliferative macrophages in PC samples compared to PRIs. LMs displayed significantly reduced B cells, with increased fractions of exhausted CD8 T cells and NK/NKT cells. Both LMs and PC showed nearly depleted plasma cells. Malignant cells largely exhibited diminished gastric lineage identity, predominantly adopting intestinal-like and mixed cell states, with the acquired expression of gastrointestinal stem-cell markers. LM cancer cells showed increased epithelial-to-mesenchymal signalling, while PC cancer cells had increased levels of aneuploidy. We observed differentially expressed cancer meta-programs and gene modules (GMs) between LMs and PC, with high GM2 expression in the PRI predicting an increased risk of distant metastases. Further analysis of GM signature genes revealed ferroptosis evasion through GPX4 upregulation during malignant progression. Functional validation via patient-derived xenografts and a novel autochthonous mouse model of GAC confirmed that genetic or pharmacological inhibition of ferroptosis resistance attenuates tumor growth and metastatic progression. Together, our mapping of malignant progression provides a rationale for targeting ferroptosis defense in combination with next-generation CAR T-cell immunotherapy as a potential avenue to overcome T cell dysfunction in advanced metastatic GAC therapy.

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Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes for advanced gastric cancer with different ferroptosis-related-scores

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