Biology subjects

Buske, C.

Publications and source records attributed to Buske, C..

4 recordsLinked to original sources

bioRxiv2025

GPR15LG binds CXCR4 and synergistically modulates CXCL12-induced cell signaling and migration

GPR15LG, a chemokine-like ligand for the G-protein coupled receptor 15 (GPR15), is abundantly expressed in the gastrointestinal mucosa and inflamed skin. Emerging evidence suggests its involvement in inflammatory disorders and cancers. This study investigates the effects of GPR15LG on the signaling and downstream functions of C-X-C chemokine receptor type 4 (CXCR4), which plays a critical role in immune cell trafficking and cancer metastasis. The results demonstrate that GPR15LG binds to the orthosteric site of CXCR4, modulating downstream signaling in a context-dependent manner. Specifically, GPR15LG enhances CXCL12-mediated CXCR4 signaling synergistically, promoting wound healing and cell migration across various cell types, including CD4+ T cells and cancer cells. These findings underscore the role of GPR15LG in inflammation and metastasis, offering potential therapeutic avenues for CXCR4-mediated diseases. TeaserGPR15LG binds CXCR4 thereby modulating CXCL12/CXCR4 signaling and immune and cancer cell trafficking.

cell biology↗

bioRxiv2023

Oncogenic RAS-Pathway Activation Drives Oncofetal Reprogramming and Creates Therapeutic Vulnerabilities in Juvenile Myelomonocytic Leukemia

Aberrant fetal gene expression facilitates tumor-specific cellular plasticity by hijacking molecular programs of embryogenesis1. Persistent fetal gene signatures in childhood malignancies are typically explained by their prenatal origins2-6. In contrast, reactivation of fetal gene expression is considered a consequence of oncofetal reprogramming (OFR) in adult malignancies and is associated with aggressive disease7-10. To date, OFR has not been described in the context of childhood malignancies. Here, we performed a comprehensive multi-layered molecular characterization of juvenile myelomonocytic leukemia (JMML) and identified OFR as a hallmark of aggressive JMML. We observed that hematopoietic stem cells (HSCs) aberrantly express mixed developmental programs in JMML. Expression of fetal gene signatures combined with a postnatal epigenetic landscape suggested OFR, which was validated in a JMML mouse model, demonstrating that postnatal activation of RAS signaling is sufficient to induce fetal gene signatures. Integrative analysis identified the fetal HSC maturation marker CD52 as a novel therapeutic target for aggressive JMML. Anti-CD52 treatment depleted human JMML HSCs and disrupted disease propagation in vivo. In summary, this study implicates OFR, defined as postnatal acquisition of fetal transcription signatures, in the pathobiology of a childhood malignancy. We provide evidence for the direct involvement of oncogenic RAS signaling in OFR. Finally, we demonstrate how OFR can be leveraged for the development of novel treatment strategies. Highlights{blacksquare} Epigenomic and transcriptomic landscape of juvenile myelomonocytic leukemia (JMML) in the context of hematopoietic development. {blacksquare}The presence of fetal transcription signatures in childhood malignancies is not indicative of a developmental maturation block. {blacksquare}High-risk JMML is characterized by oncofetal reprogramming of postnatal hematopoietic stem cells (HSCs). {blacksquare}RAS-pathway mutations induce fetal-like gene expression signatures in murine postnatal HSCs. {blacksquare}The fetal maturation marker CD52 is a novel therapeutic target in high-risk JMML.

cancer biology↗

bioRxiv2021

Acute myeloid leukemia cells are targeted by the naturally occurring CXCR4 antagonist EPI-X4

This manuscript has been withdrawn by the authors as no consent could be achieved with regard to data contribution. Based on this no agreement on authorship and/or listing in the acknowledgement section was reached. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cancer biology↗

bioRxiv2020

CXCR4 signaling is counteracted by the naturally occurring CXCR4 antagonist EPI-X 4 in Waldenstrom Macroglobulinemia

CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenstroms Macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Brutons tyrosine kinase inhibitor ibrutinib. Nevertheless, little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. Recently, the endogenous human peptide EPI-X4 was identified as a natural CXCR4 antagonist that effectively blocks CXCL12-mediated receptor internalization and suppresses the migration and invasion of cancer cells towards a CXCL12 gradient. Here, we demonstrate that EPI-X4 efficiently impairs growth of WM cells in vitro and in vivo and blocks their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by decreased expression of genes involved in MAPK signaling and energy metabolism. Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM growth, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.

cancer biology↗