Current lab members:

• Gilles PAGÈS, Research Director, DR1 Inserm
• Roser Busca: CR HC CNRS
• Sonia Martial: CR HC CNRS
• Philippe Lenormand: CRCN INSERM
• Frédéric Luciano: CRCN INSERM
• Sandy Giuliano: CRCN INSERM
• Maeva Dufies: CRCN CNRS
• Cercina Onesto: MCU UCA
• Julien Parola: Tech
• Saharnaz Sarlak: Post Doc ARC
• Meng Tsai: Post Doc ANR JCJC
• Rima Salma: Post Doc ANR JCJC
• Maeva Totobesola: Engineer ARC
• Arthur Gouraud: Engineer Cancéropole
• Olivia Rastoin: Engineer Roca Therapeutics
• Manon Teisseire: PhD FRM
• Jessy Sirera: PhD UCA
• Arthur Karaulic: PhD UCA
• Christina Cayron: Master
• Audrey Bennetot: 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.

Current Projects

Top Publications

• 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…
• 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.
• Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma
  6 février 2021 par Maeva Dufies
  Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the…
• Author Correction: VEGFC negatively regulates the growth and aggressiveness of medulloblastoma cells
  8 décembre 2020 par Manon Penco-Campillo
  A Correction to this paper has been published: https://doi.org/10.1038/s42003-020-01502-2.
• VEGFC negatively regulates the growth and aggressiveness of medulloblastoma cells
  17 octobre 2020 par Manon Penco-Campillo
  Medulloblastoma (MB), the most common brain pediatric tumor, is a pathology composed of four molecular subgroups. Despite a multimodal treatment, 30% of the patients eventually relapse, with the fatal appearance of metastases within 5 years. The major actors of metastatic dissemination are the lymphatic vessel growth factor, VEGFC, and its receptors/co-receptors. Here, we show that VEGFC is inversely correlated to cell aggressiveness. Indeed, VEGFC decreases MB cell proliferation and migration,…
• The combination of bevacizumab/Avastin and erlotinib/Tarceva is relevant for the treatment of metastatic renal cell carcinoma: the role of a synonymous mutation of the EGFR receptor
  16 janvier 2020 par Renaud Grépin
  Metastatic clear cell renal cell carcinomas (mRCC) over-express the vascular endothelial growth factor (VEGF). Hence, the anti-VEGF antibody bevacizumab/Avastin (BVZ) combined with interferon alpha (IFN) was approved for the treatment of mRCC. However, approval was lost in July 2016 due to the absence of sustained efficacy. We previously showed that BVZ accelerates tumor growth in experimental models of mRCC in mice, results in part explained by down-regulation of the phospho tyrosine…
• New CXCR1/CXCR2 inhibitors represent an effective treatment for kidney or head and neck cancers sensitive or refractory to reference treatments
  15 août 2019 par Maeva Dufies
  Clear cell Renal Cell (RCC) and Head and Neck Squamous Cell Carcinomas (HNSCC) are characterized by a pro-angiogenic/pro-inflammatory context. Despite conventional or targeted therapies, metastatic RCC and HNSCC remain incurable. Alternative treatments to reference therapies (sunitinib, a multi tyrosine kinase inhibitor for RCC or cisplatin for HNSCC) are urgently needed on relapse. Here, we described the relevance of targeting the ELR+CXCL cytokines receptors, CXCR1/2, for the treatment of…
• ERK1/2/MAPK pathway-dependent regulation of the telomeric factor TRF2
  2 juillet 2016 par Vincent Picco
  Telomere stability is a hallmark of immortalized cells, including cancer cells. While the telomere length is maintained in most cases by the telomerase, the activity of a protein complex called Shelterin is required to protect telomeres against unsuitable activation of the DNA damage response pathway. Within this complex, telomeric repeat binding factor 2 (TRF2) plays an essential role by blocking the ataxia telangiectasia-mutated protein (ATM) signaling pathway at telomeres and preventing…
• VEGF Splicing and the Role of VEGF Splice Variants: From Physiological-Pathological Conditions to Specific Pre-mRNA Splicing
  20 août 2015 par Mélanie Guyot
  During this past decade, the vascular endothelial growth factor (VEGF) pathway has been extensively studied. VEGF is a paradigm of molecular regulation since its expression is controlled at all possible steps including transcription, mRNA stability, translation, and pre-mRNA splicing. The latter form of molecular regulation is probably the least studied. This field has been neglected; yet different forms of VEGF with different sizes and different physiological properties issued from alternative…
• The relevance of testing the efficacy of anti-angiogenesis treatments on cells derived from primary tumors: a new method for the personalized treatment of renal cell carcinoma
  29 mars 2014 par Renaud Grépin
  Despite the numerous available drugs, the most appropriate treatments for patients affected by common or rare renal cell carcinomas (RCC), like those associated with the Xp11.2 translocation/transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene fusion (TFE3 RCC), are not clearly defined. We aimed to make a parallel between the sensitivity to targeted therapies on living patients and on cells derived from the initial tumor. Three patients diagnosed with a metastatic RCC (one…
• Mechanisms of resistance to anti-angiogenesis therapies
  20 mars 2013 par Sandy Giuliano
  Angiogenesis, the formation of new blood vessels from preexisting ones, provides oxygen and nutrients to actively proliferating tumor cells. Hence, it represents a critical aspect of tumor progression and metastasis. Because inhibition of angiogenesis represents a major approach to cancer treatment, the development of inhibitors of angiogenesis is a major challenge. The first FDA approved anti-angiogenic drug bevacizumab, a humanized monoclonal antibody directed against the Vascular Endothelial…

Lab News

Research Projects

Find out what projects IRCAN researchers are working on at the moment!

Platforms & Services

Find out about our platforms and services that drive our research.

Research Teams

IRCAN has a diverse research teams, tackling a wide range and resolution of topics in ageing and cancer.