TEAM 2: Oncogenesis of melanoma (team leader: Nicolas DUMAZ)

Main projects: (recent publications below)


I- Signal transduction in melanoma (N. Dumaz)

The recent discoveries in signal transduction in melanoma have allowed a better understanding of the molecular biology behind the development of melanoma. Improvement in our knowledge of alterations in signal transduction pathways in melanoma has led to the rapid development of a number of pharmacological agents that inhibit these pathways. We are studying signal transduction downstream of the oncogenes altered in these melanomas to highlight novel targets for therapies. We are also using these models to improve our understanding of the mechanisms of resistance to novel targeted therapies and find ways to circumvent them.

 

II- Characterizing melanoma Genetic Biomarkers involved in melanoma susceptibility and progression (N. Soufir, V. Descamps and N. Basset-Seguin)

Pigmentation traits as well as high ultraviolet (UV) exposure are well known risk factors for melanoma. In addition to major susceptibility genes (CDKN2A, CDK4, BAP1), several genetic markers have been identified that modulate melanoma risk. Our first aim is to further identify risk alleles for melanoma susceptibility, in order to improve this predictive test to target the population at risk of melanoma for prevention and screening. Our second aim is to characterize new major melanoma predisposing genes. Our third aim is to characterize new genetic biomarkers involved in melanoma progression and prognosis.

 

III- Targeted therapies of the tumour microenvironment (S. Mourah, C. Lebbé and D. Darmoul)

Melanoma tumours interact with, and react to, the adjacent microenvironment in a bidirectional manner through molecular signals that modulate the malignant phenotype. This microenvironment is known to promote invasion by cooperating with the tumour cells and supporting their survival, proliferation and production of proteinases essential for degrading the extracellular matrix. We are studying the melanoma microenvironment to identify novel strategies to target tumour-microenvironment interactions and also understand the influence of the microenvironment on therapeutic targeting of melanoma.


Main recent publications:

 

2016

1: Vallarelli AF, Rachakonda PS, André J, Heidenreich B, Riffaud L, Bensussan A, Kumar R and Dumaz N. TERT promoter mutations in melanoma render TERT expression dependent on MAPK pathway activation. Oncotarget. 2016 Jul 16. doi: 10.18632/oncotarget.10634.

 

2: Eisenhardt AE, Sprenger A, Röring M, Herr R, Weinberg F, Köhler M, Braun S, Orth J, Diedrich B, Lanner U, Tscherwinski N, Schuster S, Dumaz N, Schmidt E, Baumeister R, Schlosser A, Dengjel J, Brummer T. Phospho-proteomic analyses of B-Raf protein complexes reveal new regulatory principles. Oncotarget. 7(18):26628-52.

 

3: Laugier F, Delyon J, André J, Bensussan A, Dumaz N. Hypoxia and MITF regulate KIT oncogenic properties in melanocytes. Oncogene, 2016 Mar 14. doi: 10.1038/onc.2016.39

 

4: Delyon J, Varna M, Feugeas JP, Sadoux A, Yahiaoui S, Podgorniak MP, Leclert G, Mazouz Dorval S, Dumaz N, Janin A, Mourah S, Lebbé C. Validation of a preclinical model for assessment of drug efficacy in melanoma. Oncotarget, 7(11):13069-81.

 

5: Cassius C, Pages C, Lhote R, Roux J, Lavocat R, Réa D, Bagot M, Mourah S, Battistella M, Lebbé C*, Dumaz N*. Association of Vemurafenib and Pipobroman enhances BRAF-CRAF dimerisation in squamous cell carcinoma. J Invest Dermatol 136(6):1302-5. (*) Co-last senior authors.


2015

1: Nicolas Dumaz, Jocelyne André, Aurélie Sadoux, Florence Laugier, Marie Pierre Podgorniak, Samia Mourah, Céleste Lebbé. Driver Kit mutations in melanoma cluster in four hot spots. Melanoma Research 25:88-90 (link to Suppl. Data)


2: Hu HH, Kannengiesser C, Lesage S, André J, Mourah S, Michel L, Descamps V, Basset-Seguin N, Bagot M, Bensussan A, Lebbé C, Descamps L, Saiag P, Leccia MT, Bressac-de-Paillerets B, Tsalamlal A, Kumar R, Klebe S, Grandchamp B, Andrieu- Abadie N, Thomas L, Brice A, Dumaz N*, Soufir N*. PARKIN inactivation links Parkinson's disease to melanoma. J Natl Cancer Inst. 2015 Dec 17;108(3). * Co-last senior authors.

 

3: Laugier F, Finet-Benyair A, André J, Rachakonda PS, Kumar R, Bensussan A, Dumaz N. RICTOR involvement in the PI3K/AKT pathway regulation in melanocytes and melanoma Oncotarget. 6(29):28120-31.


2014

1: Fennira F, Pagès C, Schneider P, Sidina I, Viguier M, Basset-Seguin N, Madjlessi-Ezra N, Madelaine I, Bagot M, Battistella M, Porcher R, Mourah S, Lebbé C. Vemurafenib in the French temporary authorization for use metastatic melanoma cohort: a single-centre trial. Melanoma Res. 24(1):75-82.

 

2: Lauden L, Siewiera J, Boukouaci W, Ramgolam K, Mourah S, Lebbe C, Charron D, Aoudjit F, Jabrane-Ferrat N, Al-Daccak R. TGF-B-Induced (TGFBI) Protein in Melanoma: A Signature of High Metastatic Potential. J Invest Dermatol. 134(6):1675-85.

 

3: Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert C, Kannouche P, Soufir N, Sarasin A. Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations. Hum Mutat. 35(1):117-28.


4: Hu HH, Benfodda M, Dumaz N, Gazal S, Descamps V, Bourillon A, Basset-Seguin N, Riffault A, Ezzedine K, Bagot M, Bensussan A, Saiag P, Grandchamp B, Soufir N. A large French case-control study emphasizes the role of rare Mc1R variants in melanoma risk. Biomed Res Int. 2014:925716.


2013 

1: Allegra M, Giacchero D, Segalen C, Dumaz N, Butori C, Hofman V, Hofman P, Lacour JP, Bertolotto C, Bahadoran P, Ballotti R. A New KIT Mutation (N505I) in Acral Melanoma Confers Constitutive Signaling, Favors Tumorigenic Properties, and Is Sensitive to Imatinib. J Invest Dermatol. 134:173-6.

 

2: Charbel C, Fontaine RH, Malouf GG, Picard A, Kadlub N, El-Murr N, How-Kit A, Su X, Coulomb-L'hermine A, Tost J, Mourah S, Aractingi S, Gugan S. NRAS Mutation Is the Sole Recurrent Somatic Mutation in Large Congenital Melanocytic Nevi. J Invest Dermatol.134(4):1067-74.

 

3: Tauber M, Pages C, La Selva R, Schneider P, Chardin J, Osio A, Mourah S, Culine S, Vercellino L, Bagot M, Lebbé C. Vemurafenib as a neoadjuvant therapy in advanced melanoma: local tumour control, but no prevention of metastatic relapse. Eur J Dermatol. 23(5):702-3.

 

4: Chraybi M, Abd Alsamad I, Copie-Bergman C, Baia M, André J, Dumaz N, Ortonne N. Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations. Hum Pathol.44(9):1902-11.

 

5: Karkouche R, Kerob D, Battistella M, Soufir N, Hadj-Rabia S, Bagot M, Lebbé C, Bourrat E. Angiosarcoma in patients with xeroderma pigmentosum: less aggressive and not so rare? J Am Acad Dermatol. 69(3):e142-3.

 

6: Silva EF, Charreau I, Gourmel B, Mourah S, Kalidi I, Guillon B, De Castro N, Caron F, Braun J, Molina JM; ANRS 138 EASIER Study Group. Decreases in inflammatory and coagulation biomarkers levels in HIV-infected patients switching from enfuvirtide to raltegravir: ANRS 138 substudy. J Infect Dis. 208(6):892-7.

 

7: Vindrieux D, Gras B, Garcia-Belinchon M, Mourah S, Lebbe C, Augert A, Bernard D. Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts. Aging (Albany NY). 5(7):531-8.

 

8: Popova T, Hebert L, Jacquemin V, Gad S, Caux-Moncoutier V, Dubois-d'Enghien C, Richaudeau B, Renaudin X, Sellers J, Nicolas A, Sastre-Garau X, Desjardins L, Gyapay G, Raynal V, Sinilnikova OM, Andrieu N, Manié E, de Pauw A, Gesta P, Bonadona V, Maugard CM, Penet C, Avril MF, Barillot E, Cabaret O, Delattre O, Richard S, Caron O, Benfodda M, Hu HH, Soufir N, Bressac-de Paillerets B, Stoppa-Lyonnet D, Stern MH. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 92(6):974-80.

 

9: Baroudjian B, Battistella M, Mourah S, Hickman G, Pages C, Moulonguet I, Koskas F, Gaudric J, Le Maignan C, Dantal J, Bagot M, Petit A, Lebbe C. Arterial aneurysm with distal ischemia in a renal allografted patient: beware of angiosarcoma. Eur J Dermatol. 2013 Jun 1;23(3):410-1.

 

10: Kadlub N, Coudert A, Gatibelza ME, El Houmami N, Soufir N, Ruhin-Poncet B, L'hermine AC, Berdal A, Vazquez MP, Descroix V, Picard A. PTCH1 mutation and local aggressiveness of odontogenic keratocystic tumors in children: is there a relationship? Hum Pathol. 44(6):1071-8.

 

11: Hadj-Rabia S, Oriot D, Soufir N, Dufresne H, Bourrat E, Mallet S, Poulhalon N, Ezzedine E, Grandchamp B, Taïeb A, Catteau B, Sarasin A, Bodemer C. Unexpected extradermatological findings in 31 patients with xeroderma pigmentosum type C. Br J Dermatol. 168(5):1109-13.

 

12: Puntervoll HE, Yang XR, Vetti HH, Bachmann IM, Avril MF, Benfodda M, Catricalà C, Dalle S, Duval-Modeste AB, Ghiorzo P, Grammatico P, Harland M, Hayward NK, Hu HH, Jouary T, Martin-Denavit T, Ozola A, Palmer JM, Pastorino L, Pjanova D, Soufir N, Steine SJ, Stratigos AJ, Thomas L, Tinat J, Tsao H, Veinalde R, Tucker MA, Bressac-de Paillerets B, Newton-Bishop JA, Goldstein AM, Akslen LA, Molven A. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 50(4):264-70.

 

13: Aparicio T, Schischmanoff O, Poupardin C, Soufir N, Angelakov C, Barrat C, Levy V, Choudat L, Cucherousset J, Boubaya M, Lagorce C, Guetz GD, Wind P, Benamouzig R. Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients. Dig Liver Dis. 45(3):245-50.

 

14: Gabison E, Khayati F, Mourah S, Menashi S. Cell membrane vesicles as a tool for the study of direct epithelial-stromal interaction: lessons from CD147. Methods Mol Biol. 1066:103-11.

 

15: Bourillon A, Hu HH, Hetet G, Lacapere JJ, André J, Descamps V, Basset-Seguin N, Ogbah Z, Puig S, Saiag P, Bagot M, Bensussan A, Grandchamp B, Dumaz N, Soufir N. Genetic variation at KIT locus may predispose to melanoma. Pigment Cell Melanoma Res. 26(1):88-96.

 

2012

1: Milia-Argeiti E, Huet E, Labropoulou VT, Mourah S, Fenichel P, Karamanos NK, Menashi S, Theocharis AD. Imbalance of MMP-2 and MMP-9 expression versus TIMP-1 and TIMP-2 reflects increased invasiveness of human testicular germ cell tumours. Int J Androl. 35(6):835-44.

 

2: Ibarrola-Villava M, Hu HH, Guedj M, Fernandez LP, Descamps V, Basset-Seguin N, Bagot M, Benssussan A, Saiag P, Fargnoli MC, Peris K, Aviles JA, Lluch A, Ribas G, Soufir N. MC1R, SLC45A2 and TYR genetic variants involved in melanoma susceptibility in southern European populations: results from a meta-analysis. Eur J Cancer. 48(14):2183-91.

 

3: Kadlub N, Gatibelza ME, El Houmami N, Coulomb-Lhermine A, Descroix V, Ruhin-Poncet B, Soufir N, Vazquez MP, Berdal A, Picard A. [Pediatric keratocystic odontogenic tumor and nevoid basal cell carcinoma syndrome. Predictive factors for recurrence and aggressiveness]. Rev Stomatol Chir Maxillofac. 113(3):148-54.

 

4: Davies JR, Randerson-Moor J, Kukalizch K, Harland M, Kumar R, Madhusudan S, Nagore E, Hansson J, Höiom V, Ghiorzo P, Gruis NA, Kanetsky PA, Wendt J, Pjanova D, Puig S, Saiag P, Schadendorf D, Soufir N, Okamoto I, Affleck P, García-Casado Z, Ogbah Z, Ozola A, Queirolo P, Sucker A, Barrett JH, van Doorn R, Bishop DT, Newton-Bishop J. Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study. Pigment Cell Melanoma Res. 25(3):384-94.

 

5: Chung H, Hamza M, Oikonomopoulou K, Gratio V, Saifeddine M, Virca GD, Diamandis EP, Hollenberg MD, Darmoul D. Kallikrein-related peptidase signaling in colon carcinoma cells: targeting proteinase-activated receptors. Biol Chem. 393(5):413-20.

 

6: Lescaille G, Menashi S, Cavelier-Balloy B, Khayati F, Quemener C, Podgorniak  MP, Naïmi B, Calvo F, Lebbe C, Mourah S. EMMPRIN/CD147 up-regulates urokinase-type plasminogen activator: implications in oral tumor progression. BMC Cancer. 12:115.

 

7: Djaafri I, Maurice P, Labas V, Vinh J, Lemesle M, Arbeille B, Legrand C, Mourah S, Fauvel-Lafeve F. Platelet type III collagen binding protein (TIIICBP) presents high biochemical and functional similarities with kindlin-3. Biochimie. 94(2):416-26.

 

8: Arnault JP, Mateus C, Escudier B, Tomasic G, Wechsler J, Hollville E, Soria JC, Malka D, Sarasin A, Larcher M, Andr√© J, Kamsu-Kom N, Boussemart L, Lacroix L, Spatz A, Eggermont AM, Druillennec S, Vagner S, Eychène A, Dumaz N, Robert C. Skin tumors induced by sorafenib; paradoxic RAS-RAF pathway activation and oncogenic mutations of HRAS, TP53, and TGFBR1. Clin Cancer Res. 18(1):263-72.

 

9: Jung C, Colombel JF, Lemann M, Beaugerie L, Allez M, Cosnes J, Vernier-Massouille G, Gornet JM, Gendre JP, Cezard JP, Ruemmele FM, Turck D, Merlin F, Zouali H, Libersa C, Dieudé P, Soufir N, Thomas G, Hugot JP. Genotype/phenotype analyses for 53 Crohn's disease associated genetic polymorphisms. PLoS One. 7(12):e52223.

 

10: Lebbe C, Guedj M, Basset-Seguin N, Podgorniak MP, Menashi S, Janin A, Mourah S. A reliable method for the selection of exploitable melanoma archival paraffin embedded tissues for transcript biomarker profiling. PLoS One. 7(1):e29143.