Eph Receptor Tyrosine Kinases in Tumor Immunity

Shiuan, Eileen; Chen, Jin

doi:10.1158/0008-5472.can-16-1521

Cited by 57 publications

(47 citation statements)

References 53 publications

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“…Identification of metabolic targets that are selectively utilized in tumor cells may greatly improve antitumor immunity by avoiding detrimental effects on the immune cells. For example, the receptor tyrosine kinase EphA2 promotes glutamine metabolism in HER2-positive and triple-negative breast cancer cells (67,68), but it is not expressed in the T cells (69). Targeting EphA2 may selectively inhibit glutaminolysis in tumor cells while simultaneously avoiding similar effects on T cells.…”

Section: Discussionmentioning

confidence: 99%

Microenvironmental Metabolism Regulates Antitumor Immunity

et al. 2019

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Metabolic reprogramming of cancer cells and the tumor microenvironment are emerging as key factors governing tumor growth, metastasis, and response to therapies including immune checkpoint inhibitors. It has been recognized that rapidly proliferating cancer cells, tumor-infiltrating lymphocytes, and vascular endothelial cells compete for oxygen and nutrients. Tumor cells and other cell types in the microenvironment not only compete for nutrients, but they also simultaneously produce immunosuppressive metabolites, leading to immune escape. In addition, commensal microbial metabolites can influence regulatory T cells and inflammation in the intestine, thus playing an essential role in cancer prevention or cancer promotion. In this review, we summarize recent advances on metabolic interactions among various cell types in the tumor microenvironment, with a focus on how these interactions affect tumor immunity. We also discuss the potential role of blood vessel metabolism in regulating immune cell trafficking and activation.

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Section: Discussionmentioning

confidence: 99%

Microenvironmental Metabolism Regulates Antitumor Immunity

et al. 2019

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“…10F,G). EPHA2 has been previously identified as a highly expressed surface protein in OS cells and tissue [41][42][43] . We found that LGALS1, a potent inducer of T-cell apoptosis 44,45 , was LGALS1 upregulation has been reported in human OS tissue samples 46 and is associated with metastatic and aggressive cancer cell phenotypes [47][48][49] .…”

Section: Figure 5 Prm-based Confirmation Of Hypoxia-induced Expressimentioning

confidence: 99%

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

Song

Pearce

Jiang

et al. 2020

Sci Rep

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osteosarcoma (oS) is the most common bone cancer in children and young adults. Solid tumors are characterized by intratumoral hypoxia, and hypoxic cells are associated with the transformation to aggressive phenotype and metastasis. the proteome needed to support an aggressive osteosarcoma cell phenotype remains largely undefined. To link metastatic propensity to a hypoxia-induced proteotype, we compared the protein profiles of two isogenic canine OS cell lines, POS (low metastatic) and HMpoS (highly metastatic), under normoxia and hypoxia. Label-free shotgun proteomics was applied to comprehensively characterize the hypoxia-responsive proteome profiles in the OS cell phenotypes. Hypothesis-driven parallel reaction monitoring was used to validate the differential proteins observed in the shotgun data and to monitor proteins of which we expected to exhibit hypoxia responsiveness, but which were absent in the label-free shotgun data. We established a "distance" score (|z HMPOS − z POS |), and "sensitivity" score (|z Hypoxia − z Normoxia ) to quantitatively evaluate the proteome shifts exhibited by oS cells in response to hypoxia. evaluation of the sensitivity scores for the proteome shifts observed and principal component analysis of the hypoxia-responsive proteins indicated that both cell types acquire a proteome that supports a Warburg phenotype with enhanced cell migration and proliferation characteristics. Cell migration and glucose uptake assays combined with protein function inhibitor studies provided further support that hypoxia-driven adaption of pathways associated with glycolytic metabolism, collagen biosynthesis and remodeling, redox regulation and immunomodulatory proteins typify a proteotype associated with an aggressive cancer cell phenotype. Our findings further suggest that proteins involved in collagen remodeling and immune editing may warrant further evaluation as potential targets for anti-metastatic treatment strategies in osteosarcoma.

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“…2 These receptors are wellestablished mediators in cell-cell interactions and motility and are expressed in human cancers, including melanoma, prostate, breast, colon, lung and esophageal carcinomas. 3 Among these receptors, EphA2 plays important roles in oncogenesis, metastasis and treatment resistance. 4 In ES, we demonstrated the involvement of EphA2 in tumor progression by promoting angiogenesis in a ligand-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma

García-Monclús

López-Alemany

Almacellas-Rabaiget

et al. 2018

Intl Journal of Cancer

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Ewing sarcoma (ES) is the second most common bone malignancy affecting children and young adults with poor prognosis due to high metastasis incidence. Our group previously described that EphA2, a tyrosine kinase receptor, promotes angiogenesis in Ewing sarcoma (ES) cells via ligand-dependent signaling. Now we wanted to explore EphA2 ligand-independent activity, controlled upon phosphorylation at S897 (p-EphA2 ), as it has been linked to metastasis in several malignancies. By reverse genetic engineering we explored the phenotypic changes after EphA2 removal or reintroduction. Gene expression microarray was used to identify key players in EphA2 signaling. Mice were employed to reproduce metastatic processes from orthotopically implanted engineered cells. We established a correlation between ES cells aggressiveness and p-EphA2 . Moreover, stable overexpression of EphA2 in low EphA2 expression ES cells enhanced proliferation and migration, but not a non-phosphorylable mutant (S987A). Consistently, silencing of EphA2 reduced tumorigenicity, migration and invasion in vitro, and lung metastasis incidence in experimental and spontaneous metastasis assays in vivo. A gene expression microarray revealed the implication of EphA2 in cell signaling, cellular movement and survival. ADAM19 knockdown by siRNA technology strongly reproduced the negative effects on cell migration observed after EphA2 silencing. Altogether, our results suggest that p-EphA2 correlates with aggressiveness in ES, so blocking its function may be a promising treatment.

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Eph Receptor Tyrosine Kinases in Tumor Immunity

Cited by 57 publications

References 53 publications

Microenvironmental Metabolism Regulates Antitumor Immunity

Microenvironmental Metabolism Regulates Antitumor Immunity

Delineation of hypoxia-induced proteome shifts in osteosarcoma cells with different metastatic propensities

EphA2 receptor is a key player in the metastatic onset of Ewing sarcoma

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