Normal & pathological angiogenesis

Current lab members:

Gilles PAGÈS, Research Director, DRCE INSERM
Roser Busca: CR HC CNRS
Sonia Martial: CR HC CNRS
Philippe Lenormand: CRCN INSERM
Frédéric Luciano: CRCN INSERM
Sandy Giuliano: CRCN INSERM
Cercina Onesto: MCU UCA
Saharnaz Sarlak: Post Doc ARC
Meng Tsai: Post Doc ANR JCJC
Rima Salma: Post Doc ANR JCJC
Monsef Idrissi: engineer CNRS student in bioinformatics
Arthur Gouraud: Engineer Cancéropole
Olivia Rastoin: Engineer Roca Therapeutics
Manon Teisseire: PhD FRM
Jessy Sirera: PhD UCA
Arthur Karaulic: PhD UCA
Audrey Bennetot: Master
Clara Fialon: Master

Lab Alumni:

Our projects have focused on the ERK signaling pathway ; modulation of its activity, its role in tumor development (use of ERK1-/- mice) and its role in tumor angiogenesis (regulation of VEGF expression). We have highlighted regulators of VEGF expression that can serve as markers of tumor aggressiveness especially in the case of head and neck and breast cancers. We have established an original link between telomeric activity and the ERK signaling pathway. We are also interested in phenomena that could explain the varying efficiencies of Avastin/Bevacizumab (BVZ) depending on cancer origins. On models of breast and prostate cancers, the clinical efficiency of associations Taxol / BVZ could be explained by a direct effect on tumor cells expressing both VEGF and its receptor VEGF-R2. Clear cell renal cell carcinomas (RCC) express VEGF and pro-angiogenic factors of the family of ELR+CXCL cytokines. CXCL7 and CXCL8 (interleukin 8) are associated with increased mortality in patients. Monoclonal antibodies targeting CXCL7 and 8 are currently developed. In xenograft models of RCC tumors, BVZ accelerates tumor growth and induces the development of the lymphatic network that can explain the acceleration of the metastatic spread observed in patients.

Background of the team and self analysis

The group was created in 1999 when we moved from the Centre de Biochimie Parc Valrose to the Nice Cancer Centre, Centre Antoine Lacassagne (CAL). Our objectives were to decipher the links between activation of the ERK pathway and abnormal angiogenesis, two mains actors implicated in tumor development. Our localization at the CAL incited us to develop translational research aiming at reinforced the links with clinicians. My team was implicated in the discovery of new pertinent direct targets of ERK and on the molecular links between ERKs and regulation of VEGF expression at transcriptional and post transcriptional levels. Discussions with clinicians and our expertise on angiogenesis have oriented our thematic on the failure of anti-angiogenic therapies. The identification of the phosphorylation of the telomere binding factor TRF2 by ERK has established a new link between telomeric activity and activation of a major signaling pathway involved in tumor development.

Funded Projects

Publications

Aqueous humor mediator levels as biomarkers of anti-VEGF response in age-related macular degeneration
27 mars 2025 par Stéphanie Baillif
CONCLUSIONS: The aqueous humor levels of the studied mediators remained stable after anti-VEGF IVIs, except for a significant decrease in VEGF-A levels in all patients. Patients with low baseline intraocular VEGF-A levels (i.e., ≤50 pg/mL) showed an intraocular inflammatory profile with elevated IL-6, PlGF, VEGF-C, IL-8 and TNFα levels. Treatment response correlated with high baseline VEGF-A levels. An interval > 8 weeks between the third and fourth anti-VEGF IVIs was associated with a…
De Novo Serine Synthesis is a Metabolic Vulnerability that can be Exploited to Overcome Sunitinib Resistance in Advanced Renal Cell Carcinoma
3 mars 2025 par Manon Teisseire
Sunitinib is an oral tyrosine kinase inhibitor used in treating advanced renal cell carcinoma (RCC) that exhibits significant efficacy but faces resistance in 30% of patients. Identifying the molecular mechanisms underlying resistance could enable the development of strategies to enhance sunitinib sensitivity. Here, we showed that sunitinib induces a metabolic shift leading to increased serine synthesis in RCC cells. Activation of the GCN2-ATF4 stress response pathway was identified as the…
Disrupting USP39 deubiquitinase function impairs the survival and migration of multiple myeloma cells through ZEB1 degradation
30 décembre 2024 par Jessy Sirera
CONCLUSIONS: Our findings highlight the critical role of the deubiquitinase USP39, suggesting that the USP39/ZEB1 axis could serve as a potential diagnostic marker and therapeutic target in MM.
A Potent Solution for Tumor Growth and Angiogenesis Suppression via an ELR<sup>+</sup>CXCL-CXCR1/2 Pathway Inhibitor
19 juin 2024 par Oleksandr Grytsai
CXCR1/2 biomolecules play vital roles in cancer cell proliferation, tumor inflammation, and angiogenesis, making them attractive drug targets. In clear cell renal cell carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC), where CXCR1/2 is overexpressed, inhibition studies are limited. Building upon previous research efforts, we investigated new N,N'-diarylurea analogues as ELR^(+)CXCL-CXCR1/2 inhibitors. Evaluations on RCC and HNSCC cell lines and 3D spheroid cultures identified…
Unveiling CXCR2 as a promising therapeutic target in renal cell carcinoma: exploring the immunotherapeutic paradigm shift through its inhibition by RCT001
20 mars 2024 par Christopher Montemagno
CONCLUSIONS: RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
Combination of Anti-Angiogenics and Immunotherapies in Renal Cell Carcinoma Show Their Limits: Targeting Fibrosis to Break through the Glass Ceiling?
24 février 2024 par Manon Teisseire
This review explores treating metastatic clear cell renal cell carcinoma (ccRCC) through current therapeutic modalities-anti-angiogenic therapies and immunotherapies. While these approaches represent the forefront, their limitations and variable patient responses highlight the need to comprehend underlying resistance mechanisms. We specifically investigate the role of fibrosis, prevalent in chronic kidney disease, influencing tumour growth and treatment resistance. Our focus extends to…
Checkpoint inhibitors and anti-angiogenic agents: a winning combination
21 septembre 2023 par Patrick Brest
The combination of immune checkpoint inhibitors and anti-angiogenic agents is a promising new approach in cancer treatment. Immune checkpoint inhibitors block the signals that help cancer cells evade the immune system, while anti-angiogenic agents target the blood vessels that supply the tumour with nutrients and oxygen, limiting its growth. Importantly, this combination triggers synergistic effects based on molecular and cellular mechanisms, leading to better response rates and longer…
Angiogenesis and Lymphangiogenesis in Medulloblastoma Development
29 juillet 2023 par Manon Penco-Campillo
Medulloblastoma (MB) is the most prevalent brain tumor in children. Although the current cure rate stands at approximately 70%, the existing treatments that involve a combination of radio- and chemotherapy are highly detrimental to the patients' quality of life. These aggressive therapies often result in a significant reduction in the overall well-being of the patients. Moreover, the most aggressive forms of MB frequently relapse, leading to a fatal outcome in a majority of cases. However, MB is…
Should evidence of an autolysosomal de-acidification defect in Alzheimer and Parkinson diseases call for caution in prescribing chronic PPI and DMARD?
24 juillet 2023 par Sandy Giuliano
Nearly fifty million older people suffer from neurodegenerative diseases, including Alzheimer (AD) and Parkinson (PD) disease, a global burden expected to triple by 2050. Such an imminent "neurological pandemic" urges the identification of environmental risk factors that are hopefully avoided to fight the disease. In 2022, strong evidence in mouse models incriminated defective lysosomal acidification and impairment of the autophagy pathway as modifiable risk factors for dementia. To date, the…
N-terminal alanine-rich (NTAR) sequences drive precise start codon selection resulting in elevated translation of multiple proteins including ERK1/2
6 juillet 2023 par Roser Buscà
We report the discovery of N-terminal alanine-rich sequences, which we term NTARs, that act in concert with their native 5'-untranslated regions to promote selection of the proper start codon. NTARs also facilitate efficient translation initiation while limiting the production of non-functional polypeptides through leaky scanning. We first identified NTARs in the ERK1/2 kinases, which are among the most important signaling molecules in mammals. Analysis of the human proteome reveals that…
New Phenylspirodrimanes from the Sponge-Associated Fungus <em>Stachybotrys chartarum</em> MUT 3308
28 mars 2023 par Marie Dayras
Two phenylspirodrimanes, never isolated before, stachybotrin J (1) and new stachybocin G (epi-stachybocin A) (2), along with the already reported stachybotrin I (3), stachybotrin H (4), stachybotrylactam (5), stachybotrylactam acetate (6), 2α-acetoxystachybotrylactam acetate (7), stachybotramide (8), chartarlactam B (9), and F1839-J (10) were isolated from the sponge-associated fungus Stachybotrys chartarum MUT 3308. Their structures were established based on extensive spectrometric (HRMS) and…
A group of novel VEGF splice variants as alternative therapeutic targets in renal cell carcinoma
22 février 2023 par Christopher Montemagno
The efficacy of anti-angiogenic treatment by targeting VEGF/VEGF receptors in metastatic clear cell renal cell carcinoma (ccRCC) varies from patient to patient. Discovering the reasons behind this variability could lead to the identification of relevant therapeutic targets. Thus, we investigated the novel splice variants of VEGF that are less efficiently inhibited by anti-VEGF/VEGFR targeting than the conventional isoforms. By in silico analysis, we identified a novel splice acceptor in the last…
Targeting of the ELR+CXCL/CXCR1/2 Pathway Is a Relevant Strategy for the Treatment of Paediatric Medulloblastomas
11 décembre 2022 par Manon Penco-Campillo
Medulloblastoma (MB) is the most common and aggressive paediatric brain tumour. Although the cure rate can be as high as 70%, current treatments (surgery, radio- and chemotherapy) excessively affect the patients' quality of life. Relapses cannot be controlled by conventional or targeted treatments and are usually fatal. The strong heterogeneity of the disease (four subgroups and several subtypes) is related to innate or acquired resistance to reference treatments. Therefore, more efficient and…
Targeting of c-MET and AXL by cabozantinib is a potential therapeutic strategy for patients with head and neck cell carcinoma
21 septembre 2022 par Anais Hagege
Local or metastatic relapse following surgery, radiotherapy, and cisplatin is the leading cause of death in patients with head and neck squamous cell carcinoma (HNSCC). Our study shows overexpression of c-MET and AXL in HNSCC cells and patients resistant to radiotherapy and cisplatin. We demonstrate that cabozantinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), c-MET, and AXL, decreases migration, invasion, and proliferation and induces mitotic catastrophe and apoptotic…
Recent Advances in Age-Related Macular Degeneration Therapies
26 août 2022 par Marie Fabre
Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye's posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the…
Inhibiting ALK2/ALK3 Signaling to Differentiate and Chemo-Sensitize Medulloblastoma
14 mai 2022 par Doria Filipponi
CONCLUSIONS: Our work suggests that interfering with the BMP4 signaling pathway impaired the maintenance of the CSC pool by promoting cell differentiation. Hence, differentiation therapy might represent an innovative therapeutic to improve the current standard of care in MB patients.
Opposing Roles of Vascular Endothelial Growth Factor C in Metastatic Dissemination and Resistance to Radio/Chemotherapy: Discussion of Mechanisms and Therapeutic Strategies
22 avril 2022 par Christopher Montemagno
Many cancers can be cured by combining surgery with healthy margins, radiation therapy and chemotherapies. However, when the pathology becomes metastatic, cancers can be incurable. The best situation involves "chronicization" of the pathology even for several years. However, most of the time, patients die within a few months. To disseminate throughout the body, cancer cells must enter the vascular network and seed in another organ. However, during the initiation of cancer processes, the tumor is…
Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma
11 janvier 2022 par Marina Pagnuzzi-Boncompagni
CONCLUSION: Our results suggest that axitinib is a compelling candidate for MB treatment.
Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression
21 octobre 2021 par Lindsay S Cooley
CONCLUSION: A combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC.
The Polo-like kinase 1 inhibitor onvansertib represents a relevant treatment for head and neck squamous cell carcinoma resistant to cisplatin and radiotherapy
14 octobre 2021 par Anais Hagege
Rationale: Head and neck squamous cell carcinoma (HNSCC) represent the 4^(th) most aggressive cancer. 50% of patients relapse to the current treatments combining surgery, radiotherapy and cisplatin and die two years after the diagnosis. Elevated expression of the polo-like kinase 1 (Plk1) correlated to a poor prognosis in epidermoid carcinomas. Methods: The molecular links between Plk1 and resistance to cisplatin/radiotherapy were investigated in patients and cell lines resistant to cisplatin…

Lab News

Fête de la Science 2024

IRCAN was once again present at the Village des Sciences de Nice on October 11, 12 and 13 to talk about our research with: – middle and high school students […]
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New Website!

Please enjoy our new website! We want to create a imersive hub for all news and events in the fields of cancer and ageing. if you see an error, please […]
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Gilles PAGES wins the 2023 Medical Research Prize awarded by the Fondation de France

Interview (in French) with Gilles PAGES, winner of the 2023 Fondation de France « senior researcher » prize for his project on adapting treatments for elderly kidney cancer patients, at the awards ceremony on 28 March.
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Article published in Nice Matin: the discovery of a mechanism essential to the production of proteins

Nice Matin published an article on the discovery of a mechanism essential to the production of proteins essential to life made by researchers from from Gilles Pagès team. Read the full […]
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