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Project description:Symbiotic macrophage-glioma cell interactions in the tumor microenvironment reveal GBM therapeutic vulnerabilities
| PRJNA504456 | ENA
Project description:Heterotypic interactions across diverse cell types can enable tumor progression and hold the potential to expand therapeutic interventions. Here, combined profiling and functional studies of glioma cells in glioblastoma multiforme (GBM) models establish that PTEN deficiency activates YAP1, which directly upregulates lysyl oxidase (LOX) expression. Mechanistically, secreted LOX functions as a potent macrophage chemoattractant via activation of the β1 integrin-PYK2 pathway in macrophages. These infiltrating macrophages secrete SPP1, which sustains glioma cell survival and stimulates angiogenesis. In PTEN-null GBM models, LOX inhibition markedly suppresses macrophage infiltration and tumor progression. Correspondingly, YAP1-LOX and β1 integrin-SPP1 signaling correlates positively with higher macrophage density and lower overall survival in GBM patients. This symbiotic glioma-macrophage interplay provides therapeutic targets specifically for PTEN-deficient GBM.
| S-EPMC6561349 | biostudies-literature
Project description:Therapeutic targeting of tumor vulnerabilities is emerging as a key area of research. This review is focused on exploiting the vulnerabilities of tumor cells and the immune cells in the tumor immune microenvironment (TIME), including tumor hypoxia, tumor acidity, the bidirectional proton-coupled monocarboxylate transporters (MCTs) of lactate, mitochondrial oxidative phosphorylation (OXPHOS), and redox enzymes in the tricarboxylic acid cycle. Cancer cells use glucose for energy even under normoxic conditions. Although cancer cells predominantly rely on glycolysis, many have fully functional mitochondria, suggesting that mitochondria are a vulnerable target organelle in cancer cells. Thus, one key distinction between cancer and normal cell metabolism is metabolic reprogramming. Mitochondria-targeted small molecule inhibitors of OXPHOS inhibit tumor proliferation and growth. Another hallmark of cancer is extracellular acidification due lactate accumulation. Emerging results show that lactate acts as a fuel for mitochondrial metabolism and supports tumor proliferation and growth. Metabolic reprogramming occurs in glycolysis-deficient tumor phenotypes and in kinase-targeted, drug-resistant cancers overexpressing OXPHOS genes. Glycolytic cancer cells located away from the vasculature overexpress MCT4 transporter to prevent overacidification by exporting lactate, and the oxidative cancer cells located near the vasculature express MCT1 transporter to provide energy through incorporation of lactate into the tricarboxylic acid cycle. MCTs are, therefore, a vulnerable target in cancer metabolism. MCT inhibitors exert synthetic lethality in combination with metformin, a weak inhibitor of OXPHOS, in cancer cells. Simultaneously targeting multiple vulnerabilities within mitochondria shows synergistic antiproliferative and antitumor effects. Developing tumor-selective, small molecule inhibitors of OXPHOS with a high therapeutic index is critical to fully exploiting the mitochondrial vulnerabilities. We and others developed small-molecule inhibitors containing triphenylphosphonium cation that potently inhibit OXPHOS in tumor cells and tissues. Factors affecting tumor cell vulnerabilities also impact immune cells in the TIME. Glycolytic tumor cells supply lactate to the tumor-suppressing regulatory T cells overexpressing MCTs. Therapeutic opportunities for targeting vulnerabilities in tumor cells and the TIME, as well as the implications on cancer health disparities and cancer treatment, are addressed.
| S-EPMC9214210 | biostudies-literature
Project description:Gliomas, the most prevalent primary tumors in the central nervous system, are marked by their immunosuppressive properties and consequent poor patient prognosis. Current evidence emphasizes the pivotal role of the tumor microenvironment in the progression of gliomas, largely attributed to tumor-associated macrophages (brain-resident microglia and bone marrow-derived macrophages) that create a tumor microenvironment conducive to the growth and invasion of tumor cells. Yet, distinguishing between these two cell subgroups remains a challenge. Thus, our review starts by analyzing the heterogeneity between these two cell subsets, then places emphasis on elucidating the complex interactions between microglia and glioma cells. Finally, we conclude with a summary of current attempts at immunotherapy that target microglia. However, given that independent research on microglia is still in its initial stages and has many shortcomings at the present time, we express our related concerns and hope that further research will be carried out to address these issues in the future.
| S-EPMC10493873 | biostudies-literature
Project description:Amplification of the epidermal growth factor receptor gene (EGFR) represents one of the most commonly observed genetic lesions in glioblastoma (GBM); however, therapies targeting this signaling pathway have failed clinically. Here, using human tumors, primary patient-derived xenografts (PDX), and a murine model for GBM, we demonstrate that EGFR inhibition leads to increased invasion of tumor cells. Further, EGFR inhibitor-treated GBM demonstrates altered oxidative stress, with increased lipid peroxidation, and generation of toxic lipid peroxidation products. A tumor cell subpopulation with elevated aldehyde dehydrogenase (ALDH) levels was determined to comprise a significant proportion of the invasive cells observed in EGFR inhibitor-treated GBM. Our analysis of the ALDH1A1 protein in newly diagnosed GBM revealed detectable ALDH1A1 expression in 69% (35/51) of the cases, but in relatively low percentages of tumor cells. Analysis of paired human GBM before and after EGFR inhibitor therapy showed an increase in ALDH1A1 expression in EGFR-amplified tumors (P < 0.05, n = 13 tumor pairs), and in murine GBM ALDH1A1-high clones were more resistant to EGFR inhibition than ALDH1A1-low clones. Our data identify ALDH levels as a biomarker of GBM cells with high invasive potential, altered oxidative stress, and resistance to EGFR inhibition, and reveal a therapeutic target whose inhibition should limit GBM invasion.
| S-EPMC6726545 | biostudies-literature
Project description:SignificanceComprehensive single-cell proteomics analyses of lung adenocarcinoma progression reveal the role of tumor-associated macrophages in resistance to PD-1 blockade therapy. See related commentary by Lee et al., p. 2515.
| S-EPMC9296613 | biostudies-literature
Project description:The development of cancer is not just the growth and proliferation of a single transformed cell, but its tumor microenvironment (TME) also coevolves with it, which is primarily involved in tumor initiation, development, metastasis, and therapeutic responses. Recent years, TME has been emerged as a potential target for cancer diagnosis and treatment. However, the clinical efficacy of treatments targeting the TME, especially its specific components, remains insufficient. In parallel, the gut microbiome is an essential TME component that is crucial in cancer immunotherapy. Thus, assessing and constructing frameworks between the gut microbiota and the TME can significantly enhance the exploration of effective treatment strategies for various tumors. In this review the role of the gut microbiota in human cancers, including its function and relationship with various tumors was summarized. In addition, the interaction between the gut microbiota and the TME as well as its potential applications in cancer therapeutics was described. Furthermore, it was summarized that fecal microbiota transplantation, dietary adjustments, and synthetic biology to introduce gut microbiota-based medical technologies for cancer treatment. This review provides a comprehensive summary for uncovering the mechanism underlying the effects of the gut microbiota on the TME and lays a foundation for the development of personalized medicine in further studies.
| S-EPMC10844568 | biostudies-literature
Project description:Glioma is one of the most malignant and fatal tumors in adults. Researchers and physicians endeavor to improve clinical efficacy towards it but made little achievement. In recent years, people have made advances in understanding characteristics and functions of tumor microenvironment and its role in different processes of tumor. In this paper, we describe the effects of tumor microenvironment on glioma proliferation, invasion and treatments. By explaining underlying mechanisms and enumerating new therapy strategies employing tumor microenvironment, we aim to provide novel ideas to improve clinical outcomes of glioma.
| S-EPMC5558106 | biostudies-other
Project description:Mouse models and genetically engineered mouse models (GEMM) are essential experimental tools for the understanding molecular mechanisms within complex biological systems. GEMM are especially useful for inferencing phenocopy information to genetic human diseases such as breast cancer. Human breast cancer modeling in mice most commonly employs mammary epithelial-specific promoters to investigate gene function(s) and, in particular, putative oncogenes. Models are specifically useful in the mammary epithelial cell in the context of the complete mammary gland environment. Gene targeted knockout mice including conditional targeting to specific mammary cells can reveal developmental defects in mammary organogenesis and demonstrate the importance of putative tumor suppressor genes. Some of these models demonstrate a non-traditional type of tumor suppression which involves interplay between the tumor susceptible cell and its host/environment. These GEMM help to reveal the processes of cancer progression beyond those intrinsic to cancer cells. Furthermore, the, analysis of mouse models requires appropriate consideration of mouse strain, background, and environmental factors. In this review, we compare aging-related factors in mouse models for breast cancer. We introduce databases of GEMM attributes and colony functional variations.
| S-EPMC5884881 | biostudies-literature
Project description:Within the tumor microenvironment, macrophages exist in an immunosuppressive state, preventing T cells from eliminating the tumor. Due to this, research is focusing on immunotherapies that specifically target macrophages in order to reduce their immunosuppressive capabilities and promote T cell function. In this study, we develop an agent-based model consisting of the interactions between macrophages, T cells, and tumor cells to determine how the immune response changes due to three macrophage-based immunotherapeutic strategies: macrophage depletion, recruitment inhibition, and macrophage reeducation. We find that reeducation, which converts the macrophages into an immune-promoting phenotype, is the most effective strategy and that the macrophage recruitment rate and tumor proliferation rate (tumor-specific properties) have large impacts on therapy efficacy. We also employ a novel method of using a neural network to reduce the computational complexity of an intracellular signaling mechanistic model.
| S-EPMC7790427 | biostudies-literature