Ephrin Receptor A4 Expression Enhances Migration, Invasion and Neurotropism in Pancreatic Ductal Adenocarcinoma Cells

Furuhashi, Satoru; Morita, Yoshifumi; Ida, Shinya; Muraki, Ryuta; Kitajima, Ryo; Takeda, Makoto; Kikuchi, Hirotoshi; Hiramatsu, Yoshihiro; Setou, Mitsutoshi; Takeuchi, Hiroya

doi:10.21873/anticanres.14938

Cited by 9 publications

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“…This is of particular note since axon guidance genes drive the growth and migration of developing axons in the embryo and synaptic and neural plasticity of nerves ( Cho and Miller, 2002 ; Butler and Tear, 2007 ; Li and Ransohoff, 2008 ; Kolodkin and Tessier-Lavigne, 2011 ; Stoeckli, 2018 ). The study here suggests that axonal guidance molecules could have a broad role in nerve growth and PNI during tumor development and progression, which is supported by experimental research in different cancer types ( Biankin et al, 2012 ; Shao et al, 2013 ; Göhrig et al, 2014 ; Schmitd et al, 2018 ; Furuhashi et al, 2021 ; Yin et al, 2021 ).…”

Section: Discussionsupporting

confidence: 74%

“…Several studies have suggested that these molecules may have a role in nerve/tumor interactions. For instance, EPHA4A was found upregulated in a PDAC cell line (MIAPACA), which enhanced their migration and influenced neurite outgrowth in a DRG-tumor cell in vitro assay ( Furuhashi et al, 2021 ). In another study, EFNA1/EPHA2 was correlated with TNM stage and perineural invasion in adenoid cystic carcinoma of the salivary glands ( Shao et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

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Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion

González-Castrillón,

Wurmser,

Öhlund

et al. 2023

Front. Genet.

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Background: High nerve density in tumors and metastasis via nerves (perineural invasion—PNI) have been reported extensively in solid tumors throughout the body including pancreatic, head and neck, gastric, prostate, breast, and colorectal cancers. Ablation of tumor nerves results in improved disease outcomes, suggesting that blocking nerve–tumor communication could be a novel treatment strategy. However, the molecular mechanisms underlying this remain poorly understood. Thus, the aim here was to identify molecular pathways underlying nerve–tumor crosstalk and to determine common molecular features between PNI-associated cancers.Results: Analysis of head and neck (HNSCC), pancreatic, and gastric (STAD) cancer Gene Expression Omnibus datasets was used to identify differentially expressed genes (DEGs). This revealed extracellular matrix components as highly dysregulated. To enrich for pathways associated with PNI, genes previously correlated with PNI in STAD and in 2 HNSCC studies where tumor samples were segregated by PNI status were analyzed. Neurodevelopmental genes were found to be enriched with PNI. In datasets where tumor samples were not segregated by PNI, neurodevelopmental pathways accounted for 12%–16% of the DEGs. Further dysregulation of axon guidance genes was common to all cancers analyzed. By examining paralog genes, a clear pattern emerged where at least one family member from several axon guidance pathways was affected in all cancers examined. Overall 17 different axon guidance gene families were disrupted, including the ephrin–Eph, semaphorin–neuropilin/plexin, and slit–robo pathways. These findings were validated using The Cancer Genome Atlas and cross-referenced to other cancers with a high incidence of PNI including colon, cholangiocarcinoma, prostate, and breast cancers. Survival analysis revealed that the expression levels of neurodevelopmental gene families impacted disease survival.Conclusion: These data highlight the importance of the tumor as a source of signals for neural tropism and neural plasticity as a common feature of cancer. The analysis supports the hypothesis that dysregulation of neurodevelopmental programs is a common feature associated with PNI. Furthermore, the data suggested that different cancers may have evolved to employ alternative genetic strategies to disrupt the same pathways. Overall, these findings provide potential druggable targets for novel therapies of cancer management and provide multi-cancer molecular biomarkers.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion

González-Castrillón,

Wurmser,

Öhlund

et al. 2023

Front. Genet.

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“…R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ (accessed on 9 July 2023) via RStudio Version 2023.06.1+524 (RStudio Team, 2023) [24]. Survival analysis was performed for OS and RFS using the Kaplan-Meier method and analyzed using the logrank test.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Roles of Programmed Death-Ligand 1 Expression in Tumor and Stroma in Prognosis of Esophageal Squamous Cell Carcinoma

Murakami,

Booka,

Furuhashi

et al. 2024

Cancers

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The assessment of programmed death-ligand 1 (PD-L1) expression in esophageal squamous cell carcinoma (ESCC) has become increasingly important with the rise of immune checkpoint inhibitors (ICIs). However, challenges persist, including subjective interpretation and the unclear significance of staining intensity, as well as contrasting roles in tumoral and stromal regions. Our study enhances the understanding of PD-L1 in ESCCs by analyzing its expression in tumors and stroma with H-scores, highlighting its distinct clinicopathological impacts. In a retrospective cohort of 194 ESCC specimens from surgical resection, we quantified PD-L1 expression in tumoral and stromal compartments using H-scores, analyzing whole slide images with digital pathology analysis software. Kaplan–Meier analysis demonstrated that higher PD-L1 expression is significantly associated with improved postoperative overall survival (OS) and recurrence-free survival (RFS) in both tumoral and stromal areas. Multivariable analysis identified high tumoral PD-L1 expression as an independent prognostic factor for prolonged OS and RFS (HR = 0.47, p = 0.007; HR = 0.54, p = 0.022, respectively). In a separate analysis, high stromal PD-L1 expression was found to correlate with less advanced pathological stages and a prolonged response to cytotoxic chemotherapy, with no similar correlation found for ICI treatment response. This study reveals PD-L1’s contrasting role in the ESCC tumor immune microenvironment, impacting prognosis, tumor stage, and treatment response.

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“…EphA 4 belongs to a large and unique family of Erythropoietin-producing hepatocellular (Eph) receptors whose members have been shown to modulate cell morphology, adhesion, migration and invasion (60). EphA 4 activation has been previously associated with increased migration of cancer cells (61,62) and, particularly in gastric cancer, EphA 4 up-regulation has been reported as a bad prognostic factor (63-65). However, the EXTL2 KO model that displays a high motility phenotype shows decreased phosphorylation of this receptor (Fig.…”

Section: Discussionmentioning

confidence: 99%

Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion

Marques

Poças

Gomes

et al. 2022

Journal of Biological Chemistry

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Ephrin Receptor A4 Expression Enhances Migration, Invasion and Neurotropism in Pancreatic Ductal Adenocarcinoma Cells

Cited by 9 publications

References 0 publications

Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion

Dysregulation of core neurodevelopmental pathways—a common feature of cancers with perineural invasion

Contrasting Roles of Programmed Death-Ligand 1 Expression in Tumor and Stroma in Prognosis of Esophageal Squamous Cell Carcinoma

Glycosyltransferases EXTL2 and EXTL3 cellular balance dictates heparan sulfate biosynthesis and shapes gastric cancer cell motility and invasion

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