Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells

Neves, Maria G. P. M. S.; Marolda, Viviana; Mayor, Federico; Penela, Petronila

doi:10.3390/ijms231911887

Cited by 5 publications

(2 citation statements)

References 65 publications

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“…Collectively, these observations are reminiscent of recent findings indicating that the EGF receptor and the HER3/HER2 receptors signal to Erk1,2 through active CXCR4/ACKR3 even in the absence of CXCL12 (Neves et al, 2022) and suggest that components of the Ephrin/Eph systems can likewise highjack the CXCR4 signaling machinery to activate the Erk1,2 pathway.…”

Section: Gai Protein Activation a Previous Study Has Demonstrated Tha...supporting

confidence: 68%

Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

Rabbito,

Otun,

Fumagalli

et al. 2024

Preprint

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Chemokine receptor 4 (CXCR4) is a member of the chemokine receptor exclusively activated by the chemokine CXCL12. While CXCR4 regulates numerous physiological processes associated with cell migration and embryogenesis, its overexpression has been involved in various cancer types. Studies suggest that intracellular CXCR4 expression rather than CXCR4-operated signaling underlies its pro-tumorigenic functions. Given the role of GPCR interacting proteins in their trafficking and subcellular localization, we characterized the CXCR4 interactome using an affinity purification coupled to mass spectrometry (AP-MS) strategy. The most abundant protein identified in the CXCR4 interactome is Ephrin B1, a member of the Ephrin protein family that shares several functions with CXCR4, such as the regulation of cell migration and proliferation. Further studies showed that interaction between CXCR4 and Ephrin B1 is direct and enhanced by treating cell with CXCL12. They also indicated that Ephrin B1 prevents CXCR4 N-glycosylation, decreases CXCR4 cell surface expression and consistently inhibits CXCL12-induced CXCR4 coupling to Gαi1-3and the recruitment of β-arrestins 1 and 2. Conversely, Ephrin B1 signals to Erk1,2 through CXCR4 activation and mediates the decrease in Death Receptor 5 expression elicited by intracellular CXCR4. Collectively, these findings identify Ephrin B1 as a key mediator of CXCR4 tumorigenic signaling.

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Section: Gai Protein Activation a Previous Study Has Demonstrated Tha...supporting

confidence: 68%

Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

Rabbito,

Otun,

Fumagalli

et al. 2024

Preprint

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show abstract

“…Such results can partially be explained by the preferred localization of ACKR3 in intracellular compartments, e.g. endosomes (46,47). It has also been shown that ACKR3 surface expression in the same lymphoma cells is increased upon in vivo "conditioning" in subcutaneous grafts and further ex vivo isolation, without any modi cation in ACKR3 gene expression, again suggesting a particular tra cking of the receptor from intracellular compartments to the plasma membrane(48).…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous expression of the atypical chemokine receptor ACKR3 in glioblastoma patient-derived tissue samples and cell cultures.

Isci,

Kuppens,

Scalisi

et al. 2024

Preprint

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Background: Glioblastoma (GBM) is the most aggressive glial tumor of the adult brain, associated with invariably fatal outcome, and a deeper understanding of the underlying malignant mechanisms is necessary to address the current therapeutic failure. We previously demonstrated the role of the CXCL12/CXCR4 axis in GBM cell migration and resistance to ionizing radiation. The atypical receptor ACKR3, responsible for CXCL12 scavenging, was previously suggested as additional important player in the context of GBM. Methods: Flow cytometry was used on GBM cell lines and patient-derived GBM cell cultures to quantify the level of ACKR3 expression. Moreover, we have at our disposal patient- derived formalin-fixed paraffin-embedded (FFPE) tissue, which is used for immunofluorescent analysis to characterize precisely ACKR3-positive cells. We used also an orthotopic xenograft model to study the impact of ACKR3 in vivo. Finally, qPCR analysis was also realized to study different gene expression on GBM cells. Results: Following validation of our detection tools, we observed that ACKR3 is expressed within GBM patient tumor tissue, distributed in diverse cell types. In contrast to CXCR4, ACKR3 expression in patient-derived stem-like cells (GSCs) remains very low while ACKR3gene expression by tumor cells appears to be modulated by the in vivo environment. Using overexpression models, we also showed that in vitro ACKR3 had no significant effect on cell proliferation or invasion. Conclusions: Altogether, these results suggest that ACKR3 plays a minor role in malignant GBM cells, although its expression is possibly regulated by in vivo influences. The subtle and multifaceted functions ACKR3 could exert in GBM should therefore only be tackled within a comprehensive tumor microenvironment considering tumoral but also non-tumoral cells.

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Growth Factor Receptor Implications in Breast Cancer: Prospects for Their Molecular Transactivation in the Future and Obstacles for Target Therapy

Acosta-Ramos,

Segovia-Mendoza,

Olivares-Reyes

2024

Interdisciplinary Cancer Research

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Crosstalk between CXCR4/ACKR3 and EGFR Signaling in Breast Cancer Cells

Cited by 5 publications

References 65 publications

Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential

Heterogeneous expression of the atypical chemokine receptor ACKR3 in glioblastoma patient-derived tissue samples and cell cultures.

Growth Factor Receptor Implications in Breast Cancer: Prospects for Their Molecular Transactivation in the Future and Obstacles for Target Therapy

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