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Structures and expression profiles of Gas6 and Axl. (A) The growth arrest specific 6 (Gas6) protein belongs in the family of vitamin K-dependent proteins. Gas6 consists of a gamma-carboxyglutamic acid (Gla) domain, four epidermal growth factor (EGF)-like domains, and two laminin G (LG)-like domains. Axl belongs in the Tyro3, Axl, MerTK (TAM) subfamily of the receptor tyrosine kinases. Axl consists of immunoglobulin-like (IgL) domains, two fibronectin domains, and a kinase domain. (B) Axl is expressed in a number of tumor types. The Gas6/Axl signaling promotes tumor cell survival, proliferation, migration, invasion, angiogenesis, therapeutic resistance, and immune evasion. (C) Gas6 and Axl are expressed by host stromal cells, including endothelial cells, fibroblasts, osteoblasts, monocytes, platelets, natural killer (NK) cells, dendritic cells (DCs), and macrophages.
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Receptor tyrosine kinases have been shown to dysregulate a number of pathways associated with tumor development, progression, and metastasis. Axl is a receptor tyrosine kinase expressed in many cancer types and has been associated with therapy resistance and poor clinical prognosis and outcomes. In addition, Axl and its ligand growth arrest specifi...
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Citations
... One of the hallmarks of cancer is the immunosuppression of the TME. Indeed, the GAS6/AXL signaling pathway has been implicated in the promotion of immunosuppressive TMEs and immune evasion (62). Furthermore, AXL and MERTK receptors are expressed by TAMs and lead to secretion of immunosuppressive cytokines. ...
... CD44 functions as a receptor for multiple ECM components, as well as a cofactor for growth factors and cytokines, thus, acting as a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine signals and transduces signals to regulate cell-matrix adhesion, cell migration, proliferation, differentiation, and survival. Liu well known that AXL is expressed by a variety of host cells found in the TME, including several immune cell types, fibroblasts, osteoclasts, and endothelial cells (62). Our data instead, points to AXL being a potentially relevant player in EGFR-mutant TMEs. ...
Lung cancer is the leading cause of cancer deaths. Lethal pulmonary
adenocarcinomas (ADC) present with frequent mutations in the EGFR.
Genetically engineered murine models of lung cancer expedited comprehension
of the molecular mechanisms driving tumorigenesis and drug
response. Here, we systematically analyzed the evolution of tumor heterogeneity
in the context of dynamic interactions occurring with the
intermingled tumor microenvironment (TME) by high-resolution transcriptomics.
Our effort identified vulnerable tumor-specific epithelial cells,
as well as their cross-talk with niche components (endothelial cells, fibroblasts,
and tumor-infiltrating immune cells), whose symbiotic interface
shapes tumor aggressiveness and is almost completely abolished by treatment
with Unesbulin, a tubulin binding agent that reduces B cell–specific
Moloneymurine leukemia virus integration site 1 (BMI-1) activity. Simultaneousmagnetic
resonance imaging (MRI) analysis demonstrated decreased
tumor growth, setting the stage for future investigations into the potential
of novel therapeutic strategies for EGFR-mutant ADCs.
Significance: Targeting the TME is an attractive strategy for treatment of
solid tumors. Here we revealed how EGFR-mutant landscapes are affected
at the single-cell resolution level during Unesbulin treatment. This novel
drug, by targeting cancer cells and their interactions with crucial TME
components, could be envisioned for future therapeutic advancements.
... AXL is a tyrosine kinase receptor of the TAM kinase family and is overexpressed in many solid cancers, including RCC [99]. Along with its high-affinity ligand, the growth arrest-specific protein 6 (GAS6), AXL promotes tumour proliferation, survival, angiogenesis and invasion [100]. ROR2 is a member of the tyrosine kinase orphan receptor family that is important in embryologic development, albeit its role in adult tissue is unknown [101]. ...
Simple Summary
Renal cell carcinoma (RCC) is common, affecting over 400,000 patients globally each year. In limited stage disease and where surgery is a feasible therapeutic option, event free survival rates are high. In contrast, locally advanced disease is associated with frequent relapse, and up to 30% of patients present with metastatic disease. Standard of care treatments for metastatic disease include tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI), but clinical responses are variable and generally not durable. Novel cell-based immunotherapy approaches such as Chimeric Antigen Receptor T-cells (CAR-T) and T-cell receptor engineered T-cells (TCR-T) have shown efficacy in some blood cancers and are currently under evaluation in solid tumours including RCC. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies and outline how advanced engineering solutions may further enhance this therapeutic approach.
Abstract
Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.
... The Gas6/Axl signaling pathway regulates immune cell functions and has potential as a therapeutic target in cancer immunotherapy. 43 In endometrial cancer, GAS5 enhances the phagocytosis, antigen presentation, and cytotoxic T cell activation of tumorassociated macrophages and endometrial cancer cells by activating the miR-21-PTEN-AKT pathway and inhibiting YAP1. 44 In hepatocellular carcinoma, HGF exists in the immune microenvironment, stimulating tumor cell proliferation, migration, invasion, and promoting angiogenesis. ...
Purpose
Immunological regimens are an important area of research for treating multiple myeloma (MM). Plasma cells play a crucial role in immunotherapy.
Patients and Methods
In our study, we used both single-cell RNA sequencing (scRNA-seq) and bulk sequencing techniques to analyze MM patients. We analyzed each sample using gene set variation analysis (GSVA) based on immune-related gene sets. We also conducted further analyses to compare immune infiltration, clinical characteristics, and expression of immune checkpoint molecules between the H-S100A9 and L-S100A9 groups of MM patients.
Results
We identified eight subpopulations of plasma cells, with S100A9 plasma cells being more abundant in patients with 1q21 gain and 1q21 diploid. CellChat analysis revealed that GAS and HGF signaling pathways were prominent in intercellular communication of S100A9 plasma cells. We identified 14 immune-related genes in the S100A9 plasma cell population, which allowed us to classify patients into the H-S100A9 group or the L-S100A9 group. The H-S100A9 group showed higher ESTIMATE, immune and stroma scores, lower tumor purity, and greater immune checkpoint expression. Patients with 1q21 gain and four or more copies had the lowest ESTIMATE score, immune score, stroma score, and highest tumor purity. Drug sensitivity analysis indicated that the H-S100A9 group had lower IC50 values and greater drug sensitivity compared to the L-S100A9 group. Quantitative reverse transcription (RT-q) PCR showed significantly elevated expression of RNASE6, LYZ, S100A8, S100A9, and S100A12 in MM patients compared to the healthy control group.
Conclusion
Our study has identified a correlation between molecular subtypes of S100A9 plasma cells and the response to immunotherapy in MM patients. These findings improve our understanding of tumor immunology and provide guidance for developing effective immunotherapy strategies for this patient population.
... The most abundant lesion-resident population was LRM4 which was characterized by expression of Ccl8, Mrc1, Gas6, Marks, Cbr, and Folr2, a signature shared with many tumourassociated macrophages (TAM) 24, 25,26 . Other interesting genes that were differentially expressed in this population included Sepp1, Nrp1, and Igf1. ...
Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in non-hormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumour-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6 and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodelling. We also described a population of pro-resolving large peritoneal macrophages (LpM) that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open new avenues for the treatment of endometriosis.
... When it interacts with its specific ligand, GAS6, the AXL receptor influences a range of cell signaling pathways and the interaction among different elements of the tumor environment, such as cancer cells, endothelial cells, and cells of the immune system. AXL receptor's activation involves GAS6, a protein with a GLA domain, EGF-like repeats, and G domains, crucial for its interaction with AXL receptor [69,70]. The vitamin Kdependent γ-carboxylation of the GLA domains is essential for full TAM activation [71,72]. ...
This paper delves into the diverse and significant roles of curcumin, a polyphenolic compound from the Curcuma longa plant, in the context of cancer and inflammatory diseases. Distinguished by its unique molecular structure, curcumin exhibits potent biological activities including anti-inflammatory, antioxidant, and potential anticancer effects. The research comprehensively investigates curcumin’s molecular interactions with key proteins involved in cancer progression and the inflammatory response, primarily through molecular docking studies. In cancer, curcumin’s effectiveness is determined by examining its interaction with pivotal proteins like CDK2, CK2α, GSK3β, DYRK2, and EGFR, among others. These interactions suggest curcumin’s potential role in impeding cancer cell proliferation and survival. Additionally, the paper highlights curcumin’s impact on inflammation by examining its influence on proteins such as COX-2, CRP, PDE4, and MD-2, which are central to the inflammatory pathway. In vitro and clinical studies are extensively reviewed, shedding light on curcumin’s binding mechanisms, pharmacological impacts, and therapeutic application in various cancers and inflammatory conditions. These studies are pivotal in understanding curcumin’s functionality and its potential as a therapeutic agent. Conclusively, this review emphasizes the therapeutic promise of curcumin in treating a wide range of health issues, attributed to its complex chemistry and broad pharmacological properties. The research points towards curcumin’s growing importance as a multi-faceted natural compound in the medical and scientific community.
... failure (Lee et al., 2012;Kim et al., 2013;Schnegg-Kaufmann et al., 2019). Research has shown that Gas6 is expressed in host stromal cells, including fibroblasts, macrophages, and DCs within the tumor microenvironment (Tanaka and Siemann, 2020). Apart from neoplastic cells, Gas6 is detected in both luminal and basal mammary epithelial cells throughout puberty and adulthood and plays a role in the procedure of bone formation (Shiozawa et al., 2010;Mills et al., 2018). ...
Background: Endometriosis (EM) is a long-lasting inflammatory disease that is difficult to treat and prevent. Existing research indicates the significance of immune infiltration in the progression of EM. Efferocytosis has an important immunomodulatory function. However, research on the identification and clinical significance of efferocytosis-related genes (EFRGs) in EM is sparse.
Methods: The EFRDEGs (differentially expressed efferocytosis-related genes) linked to datasets associated with endometriosis were thoroughly examined utilizing the Gene Expression Omnibus (GEO) and GeneCards databases. The construction of the protein-protein interaction (PPI) and transcription factor (TF) regulatory network of EFRDEGs ensued. Subsequently, machine learning techniques including Univariate logistic regression, LASSO, and SVM classification were applied to filter and pinpoint diagnostic biomarkers. To establish and assess the diagnostic model, ROC analysis, multivariate regression analysis, nomogram, and calibration curve were employed. The CIBERSORT algorithm and single-cell RNA sequencing (scRNA-seq) were employed to explore immune cell infiltration, while the Comparative Toxicogenomics Database (CTD) was utilized for the identification of potential therapeutic drugs for endometriosis. Finally, immunohistochemistry (IHC) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were utilized to quantify the expression levels of biomarkers in clinical samples of endometriosis.
Results: Our findings revealed 13 EFRDEGs associated with EM, and the LASSO and SVM regression model identified six hub genes (ARG2, GAS6, C3, PROS1, CLU, and FGL2). Among these, ARG2, GAS6, and C3 were confirmed as diagnostic biomarkers through multivariate logistic regression analysis. The ROC curve analysis of GSE37837 (AUC = 0.627) and GSE6374 (AUC = 0.635), along with calibration and DCA curve assessments, demonstrated that the nomogram built on these three biomarkers exhibited a commendable predictive capacity for the disease. Notably, the ratio of nine immune cell types exhibited significant differences between eutopic and ectopic endometrial samples, with scRNA-seq highlighting M0 Macrophages, Fibroblasts, and CD8 Tex cells as the cell populations undergoing the most substantial changes in the three biomarkers. Additionally, our study predicted seven potential medications for EM. Finally, the expression levels of the three biomarkers in clinical samples were validated through RT-qPCR and IHC, consistently aligning with the results obtained from the public database.
Conclusion: we identified three biomarkers and constructed a diagnostic model for EM in this study, these findings provide valuable insights for subsequent mechanistic research and clinical applications in the field of endometriosis.
... [18][19][20][21] AXL is frequently overexpressed in solid tumors, such as pancreatic and breast cancers, and is associated with worse prognosis and resistance to antitumor treatments (radiotherapy, chemotherapy, and targeted therapy). 19,[21][22][23] AXL is also involved in modifying the tumor microenvironment 24 and in hijacking the immune system. 25 For example, AXL overexpression at the cancer cell surface correlates with decreased expression of the major histocompatibility complex 1 (MHC-1) and increased expression of the immune checkpoint PD-L1, leading to decreased CD8 + T-cell antitumor activity. ...
Background
For several years, the AXL tyrosine kinase receptor, a member of the Tyro3‐Axl‐Mer (TAM) family, has been considered a new strategic target in oncology. AXL overexpression is common in solid tumors and is associated with poor prognosis. In this context, the detection of a subset of circulating tumor cells (CTCs) that express AXL (AXL ⁺ CTCs) could be clinically relevant.
Methods
Immunostaining was performed to assess AXL expression in human breast cancer cell lines. The optimal conditions were established using flow cytometry. Spiking experiments were carried out to optimize the parameters of the CellSearch ® system detection test. CTC enumeration and AXL expression were evaluated in patients with metastatic breast cancer (mBC) before treatment initiation.
Results
An innovative AXL ⁺ CTC detection assay to be used with the CellSearch ® system was developed. In a prospective longitudinal clinical trial, blood samples from 60 patients with untreated mBC were analyzed to detect AXL ⁺ CTCs with this new assay. CTCs were detected in 35/60 patients (58.3%) and AXL ⁺ CTCs were identified in 7 of these 35 patients (11.7% of all patients).
Conclusion
This newly established AXL ⁺ CTC assay is a promising tool that can be used for liquid biopsy in future clinical trials to stratify and monitor patients with cancer receiving anti‐AXL therapies.
... In addition, the Gas 6/AXL signalling pathway is essential for cell invasion, cell migration and angiogenesis, highlighting AXL 28,29 . Aside from the Gas 6/AXL signalling pathway, research has revealed that genetic and pharmacological AXL inhibition can affect downstream signalling pathways such as PI3K-AKT, AK-STAT, etc 30 , which are crucial for the survival, migration, invasion, and angiogenesis of tumour cells 28 . Combining AXL inhibitors and PI3K/AKT pathway inhibitors can promote the inhibition of PI3K/AKT pathway inhibitors, which increases the rate of apoptosis and slows down the growth and proliferation of tumour cells [31][32][33] . ...
Colorectal cancer (CRC) is one of the most common cancers worldwide. Nowadays, owing to the complex mechanism of tumorigenesis, simultaneous inhibition of multiple targets is an important anticancer strategy. Recent studies have demonstrated receptor tyrosine kinase AXL (AXL) and histone deacetylase 2 (HDAC2) are closely associated with colorectal cancer. Herein, we identified five hit compounds concurrently targeting AXL and HDAC2 using virtual screening. Inhibitory experiments revealed these hit compounds potently inhibited AXL and HDAC2 in the nanomolar range. Among them, Hit-3 showed the strongest inhibitory effects which were better than that of the positive control groups. Additionally, MD assays showed that Hit-3 could bind stably to the AXL and HDAC2 active pockets. Further MTT assays demonstrated that Hit-3 showed potent anti-proliferative activity. Most importantly, Hit-3 exhibited significant in vivo antitumor efficacy in xenograft models. Collectively, this study is the first discovery of dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment.
... According to Wu et al., CD4+ exhausted T cells with high CD200/PD-1 expression levels exhibited higher expression of EMT transcription factors, including CDH11, DCN, ZEB1, ZEB2, TWIST1, and SNAI1, relative to other CD4+ T cell subclusters. In fact, this ability to induce EMT-related genes can be harvested by malignant bladder cancer cells to facilitate cancer progression, and this occurs through the GAS6-AXL axis-a signaling pathway previously implicated in tumor cell proliferation, EMT, and immune evasion [94]. Because GAS6 has the capacity to stimulate AXL-mediated chemotaxis, malignant bladder cancer cells can utilize GAS6-AXL signaling to recruit PD1hi CD200hi CD4+ exhausted T cells and indirectly promote EMT. ...
... Furthermore, bladder cancer cells have the capacity to upregulate GAS6 expression by modifying m6A via METTL3 activity. This prevents m6A from being able to suppress GAS6-mediated effects, thereby promoting the transcription of EMT-related genes and inducing cancer progression [94,95]. ...
As an immune checkpoint molecule, CD200 serves a foundational role in regulating immune homeostasis and promoting self-tolerance. While CD200 expression occurs in various immune cell subsets and normal tissues, its aberrant expression patterns in hematologic malignancies and solid tumors have been linked to immune evasion and cancer progression under pathological conditions, particularly through interactions with its cognate receptor, CD200R. Through this CD200/CD200R signaling pathway, CD200 exerts its immunosuppressive effects by inhibiting natural killer (NK) cell activation, cytotoxic T cell functions, and M1-polarized macrophage activity, while also facilitating expansion of myeloid-derived suppressor cells (MDSCs) and Tregs. Moreover, CD200/CD200R expression has been linked to epithelial-to-mesenchymal transition and distant metastasis, further illustrating its role in cancer progression. Conversely, CD200 has also been shown to exert anti-tumor effects in certain cancer types, such as breast carcinoma and melanoma, indicating that CD200 may exert bidirectional effects on cancer progression depending on the specific tumor microenvironment (TME). Regardless, modulating the CD200/CD200R axis has garnered clinical interest as a potential immunotherapeutic strategy for cancer therapy, as demonstrated by early-phase clinical trials. However, further research is necessary to fully understand the complex interactions of CD200 in the tumor microenvironment and to optimize its therapeutic potential in cancer immunotherapy.
... La sobreexpresión de AXL en cáncer ha convertido a este receptor en una diana terapéutica debido a su participación vías de proliferación, migración, angiogénesis e invasión de células cancerígenas (Tanaka & Siemann, 2020). ...
Aplicación de herramientas informáticas en el análisis químico-biológico de compuestos anticancerígenos y simulación del efecto dual en el modelo de coagulación tipo cascada Pages: 103-119 Resumen: Se seleccionaron seis compuestos con actividad anticancerígena para del factor de coagulación FXa. Para ello, los compuestos anticancerígenos fueron comparados frente a dos inhibidores gold standard de FXa, Apixabán y Rivaroxabán. Adicionalmnete, los fármacos evaluados se evaluaron frente a compuestos anticancerígenos y anticoagulantes independientes de FXa (falsos positivos) como Cumarina y frente a Doxorubicina un compuesto anticancerígeno sin actividad en la cascada de coagulación (control negativo). Se encontró que todos los fármacos estudiados tendrían potencial actividad dual, es decir actividad inhibir el FXa fue Rivaroxabán. En conclusión, tras el análisis in silico Rivaroxabán es el mejor candidato para futuras evaluaciones en modelos in vitro de la inhibición de FXa dentro de la cascada de coagulación, lo cual tendría potenciales aplicaciones en el campo químico, biológico y médico-farmacéutico. Palabras-clave: Coagulación; Cáncer; Acoplamiento; Energía; Inteligencia Application of computer tools in the chemical-biological analysis of type coagulation model Abstract: Six compounds with anticancer activity were selected for evaluation reason, anticancer compounds were compared to the gold standard inhibitors of FXa, such as Apixaban and Rivaroxaban. Additionally, the evaluated drugs were
