Pan‐cancer multi‐omics analyses reveal crosstalk between the Hippo and immune signaling pathways in the tumor microenvironment

Abstract Background Oncostatin M (OSM) has been reported to be a key regulating factor in the process of tumor development. Previous studies have demonstrated both the promotion and inhibition effects of OSM in tumors, therefore inspiring controversies. However, no systematic assessment of OSM across various cancers is available, and the mechanisms behind OSM-related cancer progression remain to be elucidated. Methods Based on The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, we conducted a pan-cancer analysis on OSM to explore its tumor-related functions across cancers as well as its correlations with specific molecules, cells in the tumor microenvironment. Considering the results of pan-cancer analysis, we chose the specific tumor glioblastoma multiforme (GBM) to screen out the OSM-induced signaling pathways and intercellular communications in tumor progression. Wound scratch assay, invasion assay and qRT-PCR were performed to verify the biological effects of OSM on glioblastoma cells. Results Higher OSM level was found in most tumor tissues compared with corresponding normal tissues, and the enhanced OSM expression was observed to be strongly related to patients’ poor prognosis in several cancers. Moreover, the expression of OSM was associated with stromal and immune cell infiltration in the tumor microenvironment, and OSM-related immune checkpoint and chemokine co-expression were also observed. Our results suggested that OSM could communicate extensively with the tumor microenvironment. Taking GBM as an example, our study found that two critical signaling pathways in OSM-related tumor progression by KEGG enrichment analysis: Jak-STAT and NF-κB pathways. Single-cell RNA sequencing data analysis of GBM revealed that OSM was mainly secreted by microglia, and cell–cell interaction analysis proved that OSM-OSMR is an important pathway for OSM to stimulate malignant cells. In vitro, OSM treatment could facilitate the migration and invasion of glioblastoma cells, meanwhile promote the proneural-mesenchymal transition. The administration of STAT3 inhibitors effectively suppressed the OSM-mediated biological effects, which proved the key role of STAT3 in OSM signaling. Conclusion Taken together, our study provides a comprehensive understanding with regard to the tumor progression under the regulation of OSM. OSM seems to be closely related to chronic inflammation and tumor development in the tumor microenvironment. As an important inflammatory factor in the tumor microenvironment, OSM may serve as a potential immunotherapeutic target for cancer treatment, especially for GBM.

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When Rab GTPases meet innate immune signaling pathways

Cytokine & Growth Factor Reviews ◽

10.1016/j.cytogfr.2021.01.002 ◽

2021 ◽

Author(s):

Chenhe Su ◽

Chunfu Zheng

Keyword(s):

Signaling Pathways ◽

Innate Immune ◽

Rab Gtpases ◽

Immune Signaling ◽

Innate Immune Signaling

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Are innate immune signaling pathways in plants and animals conserved?

Nature Immunology ◽

10.1038/ni1253 ◽

2005 ◽

Vol 6 (10) ◽

pp. 973-979 ◽

Cited By ~ 584

Author(s):

Frederick M Ausubel

Keyword(s):

Signaling Pathways ◽

Innate Immune ◽

Immune Signaling ◽

Innate Immune Signaling

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Identification and characterization of five transcription factors that are associated with evolutionarily conserved immune signaling pathways in the schistosome-transmitting snail Biomphalaria glabrata

Molecular Immunology ◽

10.1016/j.molimm.2011.05.017 ◽

2011 ◽

Vol 48 (15-16) ◽

pp. 1868-1881 ◽

Cited By ~ 28

Author(s):

Si-Ming Zhang ◽

Kristen A. Coultas

Keyword(s):

Transcription Factors ◽

Signaling Pathways ◽

Biomphalaria Glabrata ◽

Immune Signaling ◽

Evolutionarily Conserved ◽

Identification And Characterization

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Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment

Experimental Hematology and Oncology ◽

10.1186/s40164-021-00226-1 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Linbang Wang ◽

Tao He ◽

Jingkun Liu ◽

Jiaojiao Tai ◽

Bing Wang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Tumor Cell ◽

Hub Genes ◽

Tumor Associated Macrophage ◽

Molecular Features ◽

Receptor Interactions ◽

Tumor Types ◽

Pan Cancer

Abstract Background Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME). However, their contribution to the immunosuppressive status of the TME remains unclear. Methods We integrated single-cell sequencing and transcriptome data from different tumor types to uncover the molecular features of TAMs. In vitro experiments and prospective clinical tests confirmed the results of these analysis. Results We first detected intra- and inter-tumoral heterogeneities between TAM subpopulations and their functions, with CD86+ TAMs playing a crucial role in tumor progression. Next, we focused on the ligand-receptor interactions between TAMs and tumor cells in different TME phenotypes and discovered that aberrant expressions of six hub genes, including FLI1, are involved in this process. A TAM-tumor cell co-culture experiment proved that FLI1 was involved in tumor cell invasion, and FLI1 also showed a unique pattern in patients. Finally, TAMs were discovered to communicate with immune and stromal cells. Conclusion We determined the role of TAMs in the TME by focusing on their communication pattern with other TME components. Additionally, the screening of hub genes revealed potential therapeutic targets.

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Converging purinergic and immune signaling pathways drive IL-6 secretion by Fragile X cortical astrocytes via STAT3

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2021.577745 ◽

2021 ◽

pp. 577745

Author(s):

Kathryn E. Reynolds ◽

Victoria Krasovska ◽

Angela L. Scott

Keyword(s):

Signaling Pathways ◽

Fragile X ◽

Immune Signaling ◽

Cortical Astrocytes

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M6a Regulator-Associated Methylation Modification Patterns Shape Tumor Microenvironment Characteristics in Hepatocellular Carcinoma

10.21203/rs.3.rs-778749/v1 ◽

2021 ◽

Author(s):

Bobin Ning ◽

Yonggan Xue ◽

Hongyi Liu ◽

Hongyu Sun ◽

Baoqing Jia

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Single Cell ◽

Signaling Pathways ◽

Principal Component ◽

Unsupervised Clustering ◽

Survival Prediction ◽

Multiple Perspectives ◽

Single Cell Sequencing ◽

Survival Expectations

Abstract Although substantial achievements in the tumor microenvironment (TME) of hepatocellular carcinoma (HCC) have led to fundamental improvements both in the basic research and clinical management, the potential mechanisms and regulatory relationships between m6A regulators and the TME are still unknown. We first conducted unsupervised clustering on the samples according to the core m6A expression, and then compared the signaling pathways, differential genes (DEGs), and TME between the m6A phenotypes, and re-validated the relationship between m6A regulators and TME by single cell sequencing. Then, the geneCluster was obtained by another unsupervised clustering of the DEGs, and the clinical as well as TME traits were evaluated among the geneClusters. Finally, the m6A scores of individual patients were calculated by principal component analysis (PCA) to verify the correlation from multiple perspectives, including survivals, clinical characters, mutations, TME, immunotherapy, and chemotherapy. Through a comprehensive analysis of 729 samples, we classified HCC patients into three m6A clusters and three geneClusters. Each group exhibited remarkable variations in terms of signaling pathways, clinical traits, and survival expectations. Notably, the m6A phenotypes corresponded to three different types of TME, namely immune-inflamed, immune-excluded, and immune-desert, respectively. In addition, the m6A regulator can accurately reflect the individualized microenvironment in HCC, and present supreme expression levels in the stromal microenvironment. However, the m6A score system is able to make accurate predictions not only in terms of clinical traits, survival prediction, and TME mentioned above, but also in the sensitivity of HCC patients to immunotherapy and chemotherapy. This study revealed the uniqueness and pluripotency of m6A regulators in the TME of HCC by combining single-cell sequencing and bulk sequencing. The quantified m6A modification indices were able to accurately predict patient survival expectations, clinical traits, TME, and sensitivity to immunotherapy and chemotherapy.

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Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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Primary vulvar squamous cell carcinomas with high T cell infiltration and active immune signaling are potential candidates for neoadjuvant PD-1/PD-L1 immunotherapy

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003671 ◽

2021 ◽

Vol 9 (10) ◽

pp. e003671

Author(s):

Kim E Kortekaas ◽

Saskia J Santegoets ◽

Liselotte Tas ◽

Ilina Ehsan ◽

Pornpimol Charoentong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Signaling Pathways ◽

T Cell Activation ◽

Squamous Cell ◽

Molecular Subtype ◽

Cell Infiltration ◽

Immune Signaling ◽

T Cell Infiltration ◽

Expression Of Genes

BackgroundA profound insight into the immune landscape of vulvar squamous cell carcinoma (VSCC) is lacking. Here, an in-depth interrogation of T cell infiltration, local immune contexture, signaling pathways and checkpoint molecule expression was performed in early-stage and late-stage VSCC.MethodsThe type, location, and infiltration pattern of T cells were studied in 109 patients with primary VSCC FIGO stage I–III. RNA expression of genes involved in immune oncology and oncogenic signaling pathways was analyzed in 40 VSCC, matched for prognostic clinicopathological variables, analyzed for HPV and p53 status, and selected based on T cell infiltration.ResultsHigh intraepithelial infiltration with CD4 or CD8 T cells was associated with longer overall and recurrence-free survival and formed an independent prognostic factor, outperforming molecular subtype and stage of the disease. Strong T cell infiltrated VSCC displayed a coordinated immune response reflected by a positive association between T cells and different lymphocyte and myeloid cell subsets. The expression of genes involved in the migration of T cells and myeloid cells, T cell activation and costimulation, interferon (IFN)-γ signaling, cytotoxicity and apoptosis was higher than in low infiltrated tumors. An active immune signaling profile was observed in all inflamed, part of the altered-excluded and not in altered-immunosuppressed or deserted VSCC. While several checkpoint molecules were overexpressed, only PD-L1 expression displayed discriminatory ability and clinical usefulness. High PD-L1 expression was detected in all inflamed and ~60% of the altered-excluded VSCC.ConclusionAn active immune signaling profile is present in 35% of primary FIGO I–III VSCCs, suggesting potential responsiveness to neoadjuvant PD-1/PD-L1 immunotherapy.

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