Atlas of metastatic gastric cancer links ferroptosis to disease progression and immunotherapy response
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PROVIDER: PRJNA1000548 | ENA |
REPOSITORIES: ENA
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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.
2024-05-23 | GSE239676 | GEO
Project description:Despite the successful application of immunotherapy, both innate and acquired resistance are typical in melanoma. Ferroptosis induction appears to be a potential strategy to enhance the effectiveness of immunotherapy. However, the relationship between the status of ferroptosis and the effectiveness of immunotherapy, as well as viable strategies to augment ferroptosis, remain unclear. In this study, through large-scale drug screening of cardiovascular drugs, we identified propafenone, an anti-arrhythmia medication, as capable of synergizing with ferroptosis inducers in melanoma. Furthermore, we observed that propafenone, in combination with RSL3, collaboratively induces mitochondrial-associated ferroptosis. Mechanistically, propafenone transcriptionally upregulates mitochondrial HMOX1 via activation of the JNK/JUN signaling pathway under RSL3 treatment, leading to overloaded ferrous iron and ROS within the mitochondria. In xenograft models, the combination of propafenone with ferroptosis induction led to nearly complete tumor regression. Consistently, propafenone enhances immunotherapy-induced antitumor immunity and tumoral ferroptosis in tumor-bearing mice. Significantly, patients exhibiting high levels of ferroptosis/JUN/HMOX1 exhibited improved efficacy of immunotherapy and prolonged progression-free survival. These findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.
2024-10-26 | GSE279924 | GEO
Project description:CD8+ T cells activated by cancer immunotherapy execute tumor clearance mainly by inducing cell death through perforin-granzyme- and Fas/Fas ligand-pathways. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent lipid peroxide accumulation. Although it was mechanistically illuminated in vitro, emerging evidence has shown that ferroptosis may be implicated in a variety of pathological scenarios. However, the involvement of ferroptosis in T cell immunity and cancer immunotherapy is unknown. Here, we find that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumor cells, and in turn, increased ferroptosis contributes to the anti-tumor efficacy of immunotherapy. Mechanistically, IFNg released from CD8+ T cells downregulates expression of SLC3A2 and SLC7A11, two subunits of glutamate-cystine antiporter system xc-, restrains tumor cell cystine uptake, and as a consequence, promotes tumor cell lipid peroxidation and ferroptosis. In preclinical models, depletion of cyst(e)ine by cyst(e)inase in combination with checkpoint blockade synergistically enhances T cell-mediated anti-tumor immunity and induces tumor cell ferroptosis. Thus, T cell-promoted tumor ferroptosis is a novel anti-tumor mechanism. Targeting tumor ferroptosis pathway constitutes a therapeutic approach in combination with checkpoint blockade.
2019-03-16 | GSE128392 | GEO
Project description:CD8+ T cells regulate tumor ferroptosis during cancer immunotherapy
| PRJNA527311 | ENA
Project description:Compared to the well-established roles of apoptosis in tumor suppression, the roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in tumor biology remain much less understood. BRCA1-associated protein 1 (BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin, and is a tumor suppressor in several human cancers. Here, integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, including oxidative stress response, and identify cystine transporter SLC7A11 as a BAP1-repressed target gene with high relevance to BAP1-mediated tumor suppression in human cancers. Functional studies reveal that BAP1, in a DUB-dependent manner, decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression, and that BAP1 inhibits cystine uptake and promotes ferroptosis through repressing SLC7A11 expression. Finally, we show that BAP1 inhibits tumor development partly through SLC7A11, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, the results of our study show that BAP1 executes its tumor suppression function at least partly through its regulation of SLC7A11 and ferroptosis, and uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression.
2018-07-05 | GSE101987 | GEO
Project description:Propafenone facilitates mitochondrial-associated ferroptosis and synergizes with immunotherapy in melanoma
| PRJNA1175556 | ENA
Project description:Anti-PD-1 immunotherapy has been established to be greatly effective in melanoma treatment, but the low response rate and occurrence of treatment resistance significantly hinder its efficacy. Recent studies have demonstrated that IFN-γ secreted by tumor-infiltrating CD8+T cells suppresses the expression of Xc- system to induce ferroptosis of tumor cells. However, whether the escape of tumor cells from ferroptosis facilitates the resistance to immunotherapy and the upstream regulatory mechanism remain elusive. MiRNAs participate in ferroptosis execution and can be delivered systemically by nanoparticle or alternative carriers, through which obvious therapeutic effect on cancer has been obtained. Herein, through RNA sequencing, we first obtained miRNAs expression profile of melanoma cells in IFN-γ-potentiated ferroptosis.
2022-06-29 | GSE186497 | GEO
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.
2024-05-21 | PXD050328 | Pride
Project description:Cancers evade the immune system in order to grow or metastasise through the process of cancer immunoediting. While checkpoint inhibitor therapy has been effective for reactivating tumour immunity in some cancers, many solid cancers, including breast cancer, remain largely non-responsive. Understanding the way non-responsive cancers evolve to evade immunity, what resistance pathways are activated and whether this occurs at the clonal level will improve immunotherapeutic design. We tracked cancer cell clones during the immunoediting process and determined clonal transcriptional profiles that allow immune evasion in murine mammary tumour growth in response to immunotherapy with anti-PD1 and anti-CTLA4. Clonal diversity was significantly restricted by immunotherapy treatment at both the primary and metastatic sites. These findings demonstrate that immunoediting selects for pre-existing breast cancer cell populations, that immunoediting is not a static process and is ongoing during metastasis and immunotherapy treatment. Isolation of immunotherapy resistant clones revealed unique and overlapping transcriptional signatures. The overlapping gene signature was predictive of poor survival in basal-like breast cancer patient cohorts. Some of these overlapping genes have existing small molecules which can be used to potentially improve immunotherapy response.
2021-09-01 | E-MTAB-10027 | biostudies-arrayexpress
Project description:Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines were constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines were identified. The expression of SOX13/SCAF1 was manipulated in GC cell lines where relevant biological and molecular analyses were performed. Molecular docking and computational screening were performed to screen potential inhibitors of SOX13. We showed that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics, NADPH production and chemo- and immune-resistance. Zanamivir, reverted the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Overall, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.
2023-11-17 | GSE247870 | GEO