Alumni
Stephie Anbuhl – ESR 1
PhD to be defended on 10 December 2024
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Sophie Bérenger – ESR 2
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Omolade (Ola) Otun – ESR 3
PhD to be defended on 28 November 2024
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Pietro Cocchiara – ESR 4
Project: Development of CXCR4 and CXCR7 specific chemokines and reagents
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I investigated the potential role of the non-chemokine peptide adrenomedullin and its possible interactions with CXCR4 and ACKR3. This small peptide seems to inhibit specific signalling pathways of CXCR4, for which it could act as a biased negative allosteric modulator.
Thesis: PhD defended on 17 April 2024
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ONCORNET 2.0 has been an exciting journey and a life experience I am glad I did. It burst my scientific career and helped me growing as a scientist and as an individual, thanks to all the amazing people which made this multicultural team great to work with, and the networking opportunities offered by this project.
Dehan Comez – ESR 5
Project: Spatial organisation of CXCR4 and ACKR3 receptors and complexes with growth factor receptors
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We investigated the pharmacology of CXCXR4/EGFR complex which are members of G-protein coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs), two prominent receptor families regulating various cellular processes in normal physiology and cancer progression. Additionally, the dynamics of various receptor selective agonists/antagonists (CXCL12, EGF, TGF-α, AMD3100, IT1t, Erlotinib, etc.) and nanobodies (VUN400, Q44, etc.) binding at CXCR4/EGFR complex and their monomerising or dimerising effects were studied. These data improved our understanding of CXCR4/EGFR complex and its potential therapeutic utilization especially for cancer biology.
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Ziming Wang – ESR 6
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Justyna Adamska – ESR 7
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Noureldine Youssef – ESR 8
Project: : Conformational signatures of CXCR4/ACKR3 activation in β-arrestin-1 and –2
Results: Using protein-protein interaction assays, we determined that ACKR3 can recruit both β-arrestin-1 and –2 when activated, while CXCR4 can only recruit β-arrestin-2. Furthermore, ACKR3 activation can induce conformational changes within β-arrestin-2, while CXCR4 activation cannot. Additionally, the two main activators of ACKR3 in the human body, CXCL11 and CXCL12, induce distinct β-arrestin-2 conformational change patterns. Small molecule and natural agonists for ACKR3 were found to replicate these distinct β-arrestin-2 conformations to various degrees.
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Quote: ONCORNET2.0 was a unique scientific and collaborative opportunity in state-of-the-art research in the molecular biology of cancer, but also a rich experience on the personal level. It was a great opportunity to collaborate with colleagues and group leaders from different disciplines and backgrounds as we work on a common goal in real-time.”
Alessandro Rabbito – ESR 9
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I have characterized the effects that ephrin b1 has on CXCR4 and its oncogenic potential. Furthermore, the phosphoproteome induced by CXCR4 and ACKR3 has been deciphered, opening to new perspectives in understanding their potential oncogenic signalling.
Thesis: PhD defended on 26 June 2024
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Oncornet was an amazing life experience. I had the opportunity to do good science, meet a lot of people in GPCR field, improve my scientific skills, and have fun with new friends, all in one.
Claudia Perez – ESR 10
PhD defended on 18 October 2024
Projects: Functional consequences phosphorylation barcoding/oligomerization CXCR4 and ACKR3
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I investigated the non-canonical behavior of two GPCRs, the chemokine receptors CXCR4 and ACKR3. Nanobodies were employed as research tools to evaluate and further delineate the roles of these receptors. We demonstrated that the oligomerization status of CXCR4 can be modulated, allowing us to increase oligomers and induce monomerization of CXCR4. Additionally, we developed methods to detect the oligomerization status without altering it. This oligomerization modulation may have clinical potential for targeting cancers with high CXCR4 expression that signal via the JAK2/STAT3 pathway. The anti-tumorigenic effects of these nanobodies are the next step, which may offer potential therapeutic applications. Regarding ACKR3, new tools, including phospho-mutants, novel nanobodies with unique modes of action, and the TurboID-knock-in cell line, were developed to study ACKR3. These tools successfully elucidated how ACKR3 is regulated by GRKs, how it engages with β-arrestins and its trafficking. The nanobodies further allowed us to explore ACKR3 basal activity. Finally, the interactome analysis provided initial insights into potential pathways modulated by ACKR3. Overall, our results open new research opportunities to explore the therapeutic potential of CXCR4 oligomers and ACKR3 in cancer and other relevant malignancies.
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My PhD journey has been an incredible rollercoaster, and it would not have been possible without the amazing ONCORNET people who have supported and guided me along the way. Being part of the ONCORNET 2.0 consortia was the best part of this PhD which allowed me to grow personally and professionally and build an amazing network of great people and scientists, truly thankful for this community.
Noemi Karsai – ESR 11
PhD defended on 13 September 2024
Project: Compartmentalised signalling and trafficking of CXCR4 and ACKR3
Results: Our data provided insight into the distinct dynamics and organisation of CXCR4 and ACKR3 at the plasma membrane under basal and ligand-induced conditions at various scales, using advanced fluorescence spectroscopy techniques. Additionally, our findings obtained with GRK depletion cell lines demonstrated a potential GRK role in ACKR3 localisation and trafficking post-internalisation.
Quote: ONCORNET 2.0 was an incredible PhD experience, surrounded by a supportive team and filled with inspiring teamwork. It provided fantastic networking and learning opportunities, and I’m grateful to have been a part of it.
Kylie Pan – ESR 12
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Viviana Marolda- ESR 13
Project: CXCR4/ACKR3/GRK2-governed networks in cancer cell migration and metastasis
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We found that CXCR4 or ACKR3 and GRK2/Lyn module participated in the migration of cancer cells. Additionally, our data on the possible functional interactions of the GRK2/Lyn module and the role of extracellular matrix (ECM) stiffness in this interaction, indicate potential implications in cancer cell invasion and reprogramming.
Quote: “We are only as strong as we are united, as weak as we are divided” [Cit. from Harry Potter and the Goblet of Fire]. This is what I learned from ONCORNET, to be united as a science community, always learn from each other, and obviously always cite the sources.
Gabriela Cuesta Margolles – ESR 14
Project: Contribution of ACKR3, the CXCL12 atypical chemokine receptor, to skin homeostasis
Results: We have shown the pattern of expression of ACKR3 in human keratinocytes and fibroblasts using 3D epithelial cultures that mimic the skin epidermis and dermis. The modulation of endogenous ACKR3 with different small molecules developed in the ONCORNET consortium showed the need for proper ACKR3 activation for epithelium development. ACKR3 in the dermal fibroblasts was shown to regulate CXCL12 availability, being this chemokine essential for their survival when exposed to external stressors, potentially via CXCR4. Taken together, our data propose ACKR3 as a key regulator of fibroblast-keratinocyte crosstalk and of the CXCR4/CXCL12 signaling axis, being essential for skin homeostasis.
Thesis: Contribution d’ACKR3, le récepteur atypique de la chimiokine CXCL12, à l’homéostasie de la peau et au contrôle du cycle de vie du papillomavirus humain
Quote: ONCORNET 2.0 was all about great scientific exchange, networking, learning, advice, support, and endless stickers. I don’t think you can offer me a better opportunity to do the PhD. Initiatives like these are what keep the European scientific community together.
Sneha Saha – ESR 15
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Christie Palmer – ESR 16
PhD defended on 17 July 2024
Project: Multidimensional regulation of the opioid network by ACKR3
Results: We uncovered two novel ligands for ACKR3, extending its functions beyond chemokine and opioid peptide scavenging. We introduced the family of atypical opioid receptors (AORs), which includes ACKR3, and which could serve as alternative targets for the safer treatment of opioid-related disorders (e.g. pain, depression, anxiety). This was supported by our study on conolidine, a natural compound which mediates analgesia potentially through ACKR3 modulation. We also showed that ACKR3 is released in extracellular vesicles which retain the ability to scavenge chemokines and opioid peptides, and that this release is enhanced upon ligand-binding. Finally, we also describe GPR182 as a scavenger for several peptide families (apelins, PACAPs and opioids) in addition to its recently describe chemokine scavenging function.
Quote:“Networks like ONCORNET2.0 are likely among the greatest strengths of the European scientific community, fostering a spirit of collaboration and generosity that can sometimes be scarce in academia. I was incredibly fortunate to be a part of this consortium which taught me immensely both scientifically and in terms of personal development.”
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Contact details
Please contact us at:
e.v.langemeijer@vu.nl
ONCORNET Coordinator
Vrije Universiteit Amsterdam
