Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling

Wang, Hao; Hou, Wei; Perera, Aldeb; Bettler, Carlee; Beach, Jordan R.; Ding, Xianzhong; Li, Jun; Denning, Mitchell F.; Dhanarajan, Asha; Cotler, Scott J.; Joyce, Cara; Yin, Jun; Ahmed, Fowsiyo; Roberts, Lewis R.; Qiu, Wei

doi:10.1016/j.celrep.2021.108765

Cited by 34 publications

(29 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ALW-II-41-27 is a potent EphA2 inhibitor, which has displayed antitumoral activity in different tumor types and preclinical models. In particular, ALW-II-41-27 has been studied in non-small cell lung cancer [ 48 , 49 ], breast cancer [ 50 ], gastric cancer [ 51 ], colorectal cancer [ 52 ] and hepatocellular carcinoma [ 53 ]. However, this is the first time in which ALW-II-41-27 has been studied in bone sarcomas.…”

Section: Discussionmentioning

confidence: 99%

EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

Giordano

Merlini

Ferrero

et al. 2021

Cells

View full text Add to dashboard Cite

Bone sarcomas are a group of heterogeneous malignant mesenchymal tumors. Complete surgical resection is still the cornerstone of treatment, but, in the advanced/unresectable setting, their management remains challenging and not significantly improved by target- and immuno-therapies. We focused on the tyrosine kinase Eph type-A receptor-2 (EphA2), a key oncoprotein implicated in self-renewal, angiogenesis, and metastasis, in several solid tumors and thus representing a novel potential therapeutic target. Aiming at better characterizing its expression throughout the main bone sarcoma histotypes, we investigated EPHA2 expression in the Cancer Cell Lines Encyclopedia and in public datasets with clinical annotations. looking for correlations with molecular, histopathological and patients’ features and clinical outcomes in a total of 232 osteosarcomas, 197 Ewing’s sarcomas, and 102 chondrosarcomas. We observed EPHA2 expression in bone sarcoma cell lines. We demonstrated higher EPHA2 expression in tumor tissues when compared to normal counterparts. A significant correlation was found between EPHA2 expression and Huvos grade (osteosarcoma) and with worse overall survival (dedifferentiated chondrosarcoma). Next, we characterized EPHA2 expression and activation in bone sarcoma primary tissues and in patient-derived xenografts generated in our laboratory to verify their reliability as in vivo models of osteosarcoma, Ewing’s sarcoma and chondrosarcoma. Furthermore, for the first time, we demonstrated EPHA2 expression in chondrosarcoma, suggesting its potential key role in this histotype. Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas.

show abstract

Section: Discussionmentioning

confidence: 99%

EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

Giordano

Merlini

Ferrero

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Here we show that activation of the β-glucan receptor EphA2 represses IL-23 secretion suggesting that β-glucan recognition stimulates IL-23 expression via Dectin-1/TLR-2 98 , but limits the cytokine secretion via non-classical β-glucan recognition. EphA2 activates JAK1/STAT3 signaling 99 Subject details. For in vivo animal studies, age-and sex matched mice were used.…”

Section: Discussionmentioning

confidence: 99%

“…Here we show that activation of the β-glucan receptor EphA2 represses IL-23 secretion suggesting that β-glucan recognition stimulates IL-23 expression via Dectin-1/TLR-2 98 , but limits the cytokine secretion via non-classical β-glucan recognition. EphA2 activates JAK1/STAT3 signaling 99 , and STAT3 deficient DCs exhibit increased IL-23 production after stimulation 100 . Accordingly, EphA2 deficient DCs and inhibition of JAK signaling in β-glucan stimulated DCs increase IL-23 secretion.…”

Section: Discussionmentioning

confidence: 99%

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

Millet

Solis

Aquilar

et al. 2021

Preprint

View full text Add to dashboard Cite

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. However, the complex interplay between protective antifungal immunity and immunopathology remains incompletely understood. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that Epha2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 limits IL-23 secretion in dendritic cells, while IL-23 signaling prevents ferroptotic myeloid cell death during infection. Further, ferroptosis aggravates inflammation during infection, while at the same time reducing the fungal killing capacity of macrophages. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

show abstract

“…Unlike other Eph receptors, EphA2 is widely expressed in a variety of tissues or cell lines of epithelial origin in humans, and it is expressed at extremely low levels under normal conditions [ 1 , 6 , 7 ]. Evidence from numerous clinical studies indicates that EphA2 is highly expressed in a variety of epithelium-originated malignant tumors, including hepatocellular carcinoma [ 8 ], non-small cell lung cancer [ 9 ], prostate cancer [ 10 ], breast cancer [ 11 ], colorectal cancer [ 12 ], gastric cancer [ 13 ], cervical cancer [ 14 ], and cutaneous melanoma [ 15 ]. The importance of the expression pattern, localization, and function of EphA2 in multiple types of malignancies makes it an attractive therapeutic target, and it is also an important target for the delivery of drugs, toxins, and imaging agents to tumor tissues [ 16–18 ].…”

Section: Introductionmentioning

confidence: 99%

Fully human recombinant antibodies against EphA2 from a multi-tumor patient immune library suitable for tumor-targeted therapy

Yang

Nian

et al. 2021

Bioengineered

View full text Add to dashboard Cite

Enhanced EphA2 expression is observed in a variety of epithelial-derived malignancies and is an important target for anti-tumor therapy. Currently, Therapeutic monoclonal antibodies against immune checkpoints have shown good efficacy for tumor treatment. In this study, we constructed an immune single-chain fragment variable (scFv) library using peripheral blood mononuclear cells (PBMCs) from 200 patients with a variety of malignant tumors. High affinity scFvs against EphA2 can be easily screened from the immune library using phage display technology. Anti-EphA2 scFvs can be modified into any form of recombinant antibody, including scFv-Fc and full-length IgG1 antibodies, and the recombinant antibody affinity was improved following modification. Among the modified anti-EphA2 antibodies the affinity of 77-IgG1 was significantly increased, reaching a pmol affinity level (10 −12 ). We further demonstrated the binding activity of recombinant antibodies to the EphA2 protein, tumor cells, and tumor tissues using macromolecular interaction techniques, flow cytometry and immunohistochemistry. Most importantly, both the constructed scFvs-Fc, as well as the IgG1 antibodies against EphA2 were able to inhibit the growth of tumor cells to some extent. These results suggest that the immune libraries from patients with malignant tumors are more likely to screen for antibodies with high affinity and therapeutic effect. The constructed fully human scFv immune library has broad application prospects for specific antibody screening. The screened scFv-Fc and IgG1 antibodies against EphA2 can be used for the further study of tumor immunotherapy.

show abstract

Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling

Cited by 34 publications

References 94 publications

EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing’s Sarcoma and Chondrosarcoma

IL-23 signaling prevents ferroptosis-driven renal immunopathology during candidiasis

Fully human recombinant antibodies against EphA2 from a multi-tumor patient immune library suitable for tumor-targeted therapy

Contact Info

Product

Resources

About