Gaston-Massuet, Carles

Group Leader and Senior Lecturer in Genetics and Endocrinology

I graduated in Biomedical Sciences from Barcelona University, and after an exchange programme in King’s College London, I undertook a PhD in Developmental molecular biology and study congenital birth defects of the central nervous system in Professor Andrew Copp’s laboratory at the prestigious University College London. After my PhD I joined the group of Professor Mehul Dattani and Dr. Juan Pedro Martinez-Barbera  to study congenical abnormalities of hypothalamic-pituitary axis development. In 2009 I was awarded a Research Fellowship from the National Institute of Health Research-Biomedical Research Centre to expecialise on rare endocrine disease in children such as study the molecular characterisation of a neglected paediatric tumour called adamantinomatous cranyoparhyngioma and the identification of genes that cause congenital forms of hypothalamic-pituitary dysfunction in children.

In February 2013 I was awarded a prestigious Early Career Fellowship through an open bases competition for Queen Mary University and San Barthelme’s NHS trust, to start my own independent laboratory research at the Centre for Endocrinology within William Harvey Research Institute. Since 2013 I have been successful in obtaining external funding from several grant funding bodies and Research Councils among others : Action Medical Research for Sick Children; Bart and The London Strategic Grant, Barts Cancer Institute, Children with Cancer research UK,  MRC-PhD studentships, Rose-Tree Grant, Marie-Curie WHRI-Co-Fund Starting Grant from Society of Endocrinology, Summer Studentship from Society of Endocrinology,  British Society for Neuroendocrinology, Joan Adams Fellowships and several grants as co-applicant for large grants Medical Research Council (co-applicant with Professor Marta Korbonits). Since 2013, I was awarded the Fellow of Higher Education Academy of the UK (Distinction), from the Institute of Learning University of London and I was promoted to my current position as Group Leader & Senior Lecturer in Genetics and Endocrinology in 2016. 

Summary of Research

Laboratory research vision: 

The hypothalamic-pituitary (HP-axis) is critical for life as it regulates body homeostasis through the secretion of hormones that control vital biological functions such as metabolism, fertility, reproduction, stress response, lactation, growth and electrolyte balance among others. Aberrant pituitary function often results from abnormal development of the hypothalamic-pituitary axis, leading to congenital hypopituitarism, characterised by absent or low-level secretion of one or more hormones. The molecular mechanisms that dictate the congruent development of the HP-axis, and how these mechanisms interact to create a master regulator of body homeostasis is not understood. Moreover, how this adult organ adapts its plasticity to meet endocrine challenges such as pregnancy or obesity remains unknown. Within my laboratory, we have identified key genes that are important in the development and homeostasis of this endocrine master regulator. We have discovered that the Wnt/beta-catenin pathway is critical for the maintenance of the progenitor pituitary pool and that mutations within genes of this pathway lead to severe endocrine diseases such as paediatric pituitary tumours or congenital hypopituitarism. Our research focuses on understanding how beta-catenin-mediated signalling interacts with genes that regulate hormone terminal differentiation. We have identified crosstalk between the Wnt/beta-catenin pathway and Eph-EphrinB signalling that mediates cellular differentiation of hormone-producing cells and adult organ homeostasis. Through the identification of these key molecular regulators, we have discovered genes that play a critical role in diseases such as infertility, growth restriction and pituitary tumours in humans. Unravelling how these molecules orchestrate the congruent development and maintenance of endocrine cells under hypothalamic inputs will allow us to understand the aetiology of complex congenital hypothalamic-pituitary conditions.

Directed funded projects:

1) Molecular targeted therapies to craniopharyngioma: Adamantinomatous craniopharyngioma (ACP) are pituitary tumors that affect mainly children, are locally invasive and often affect the hypothalamus and optic nerve, leading to severe endocrine dysfunction and high morbidity. Using a transgenic approach, we have generated a murine model that demonstrates that over-activation of Wntsignaling pathway results in ACPs. We are using this model to pharmacologically identify novel therapeutic treatments for these tumors. 

2) Identification of novel candidate genes important in HP axis development and hypopituitarism: From a genetic screen we have identified that the Eph:EphrinBs pathway has a role in both hypothalamic-pituitary development and Wnt-mediated tumorigenesis. Using tissue-specific transgenic modification, we are establishing the requirement for Eph:EphrinBs in HP development and assessing its role in oncogenic hypothalamic-pituitary tumorigenesis.

Molecular mechanisms that regulate the development of HP-axis and tumour formation: A) Expression of the HP-axis stem cell progenitor Sox2 (red) co-localises with EphrinB2-GFP(green). B) GFP Knock-in allele of EphrinB2 shows expression of these molecules in murine stem cell compartment of the central nervous system and skin inner ear C) Mutations in early component Wnt/-catenin pathways in the stem cells from (A) lead to endocrine tumours (C cranipharyngioma) which can become aggressive and infiltrative when mutation in EphrinB2 are present (C). 

Members of the Group

Developmental Genetics and Tumorgeneis Group  

Ms Valeria Scagliotti, Research Assistant, PhD Student
Ms Angelica Gualtieri, Research Assistant
Ms Maria Lillina Vignola, Research Assistant
Dr Fernando Jimenez, PhD, Action Medical Research-Postdoctoral Research, Marie-Curie Co-Fund Fellow, Endocrine Early Career Grant
Dr Nikolina Kyprianou, BTLC Clinical Fellowship
Dr Rachael Tan, Joan Adams Clinical Fellow
Mr James Gervace Nicholson, MRC-PhD Studentship
Ms Lorena Perez-Gutierrez, Master Research in Biotechnology
Ms Ana Alonso-Carriazo Fernández, Fourth Year Undergraduate Madrid University 
Ms Eugenia Marinelli, Erasmus student  

Co-supervisors: Professor Marta Korbonits (m.korbonits@qmul.ac.uk)

Dr Antonia Solomou, PhD, MRC funded Postdoctoral Researcher 
Dr Alejandro Ibáñez-Costa, PhDMarie-Curie Co-fund Postdoctoral Researcher 

 

Key Publications

For a full list of publist pulications click here

Gaston-Massuet, C., McCabe, M.J., Scagliotti. V.,  Gregory L, An ChWu., Jaques, T.S., Gerrelli, D., Farooqi, I.S., Raza, J., Dattani, M.T., Martinez-Barbera, J.P. Transcription factor 7-like 1 is involved in hypothalamic pituitary axis development in mice and humans. Proc Natl Acad Sci USA 2011. 2016 Feb 2;113 (5):E548-57. 

Scagliotti, V., Avagliano, L., Graziola, F., Gualtieri, A., Doi., P, Buftamante, G., Jacques TS.,Korbonits, M, Massa V,Gaston-Massuet, C. Histopatological and molecular characterisation of a new form of  intrauterine diagnosed congenital Craniopharyngioma. Pituitary September. 2635026. 

Avagliano L, Doi P, Tosi D, Scagliotti V, Gualtieri A, Gaston-Massuet C, Pistocchi A, Gallina A, Marconi AM, Bulfamante G, Massa V.Cell death and cell proliferation in human spina bifida. Birth Defects Res A Clin Mol Teratol. 2015 Dec 10. doi: 10.1002/bdra.23466. 

Fazio G*, Gaston-Massuet C*, Bettini LR, Graziola F, Scagliotti V, Cereda A, Ferrari L, Mazzola M, Cazzaniga G, Giordano A, Cotelli F, Bellipanni G, Biondi A, Selicorni A, Pistocchi A, Massa V. CyclinD1 Down-Regulation and Increased Apoptosis Are Common Features of Cohesinopathies. J Cell Physiol. 2016 Mar;231(3):613-22. * Co-joint first author

Gregory, L. C., Gaston-Massuet, C., Andoniadou, C. L., Carreno, G., Webb, E. A., Kelberman, D., McCabe, M. J., Panagiotakopoulos, L., Saldanha, J. W., Spoudeas, H. A., Torpiano, J., Rossi, M., Raine, J., Canham, N., Martinez-Barbera, J. P., and Dattani, M. T. (2014) The role of the sonic hedgehog signalling pathway in patients with midline defects and congenital hypopituitarism. Clinical endocrinology 

McCabe MJ, Hu Y, Gregory LC, Gaston-Massuet C, Alatzouglou Ks, Saladanha JW, Gualtierri A, Thankomony A, Huges I, Townshend S, Martinez-Barbera JP, Bouloux PM, Dattani MT. Novel application of liciferase assay for the in vitro functional assessment of KAL1 variants in three female with speto-optic dysplasiaMol Cell Endo 2015 Dec 5;417:63-72. 

Andoniadou, C. L., Matsushima, D., Mousavy Gharavy, S. N., Signore, M., Mackintosh, A. I., Schaeffer, M., Gaston-Massuet, C., Mollard, P., Jacques, T. S., Le Tissier, P., Dattani, M. T., Pevny, L. H., and Martinez-Barbera, J. P. (2013) Sox2(+) stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell stem cell 13, 433-445

Gaston-Massuet, C*., McCabe, M. J*., Gregory, L. C., Alatzoglou, K. S., Tziaferi, V., Sbai, O., Rondard, P., Masumoto, K. H., Nagano, M., Shigeyoshi, Y., Pfeifer, M., Hulse, T., Buchanan, C. R., Pitteloud, N., Martinez-Barbera, J. P., and Dattani, M. T. (2013) Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia. J.Clin.Endocrinol.Metabolism 98, E547-557 *Equal Contribution.  

Jayakody, S. A., Andoniadou, C. L., Gaston-Massuet, C., Signore, M., Cariboni, A., Bouloux, P. M., Le Tissier, P., Pevny, L. H., Dattani, M. T., and Martinez-Barbera, J. P. (2012) SOX2 regulates the hypothalamic-pituitary axis at multiple levels. The Journal of clinical investigation 122, 3635-3646

Andoniadou, C. L., Gaston-Massuet, C., Reddy, R., Schneider, R. P., Blasco, M. A., Le Tissier, P., Jacques, T. S., Pevny, L. H., Dattani, M. T., and Martinez-Barbera, J. P. (2012) Identification of novel pathways involved in the pathogenesis of human adamantinomatous craniopharyngioma. Acta neuropathologica 124, 259-271

Andoniadou, C. L., Signore, M., Sajedi, E., Gaston-Massuet, C., Kelberman, D., Burns, A. J., Itasaki, N., Dattani, M., and Martinez-Barbera, J. P. (2007) Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development 134, 1499-1508

Gaston-Massuet, C*., McCabe, M*. J., Tziaferi, V., Gregory, L. C., Alatzoglou, K. S., Signore, M., Puelles, E., Gerrelli, D., Farooqi, I. S., Raza, J., Walker, J., Kavanaugh, S. I., Tsai, P. S., Pitteloud, N., Martinez-Barbera, J. P., and Dattani, M. T. (2011) Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects, and hypothalamo-pituitary dysfunction. J.Clin.Endocrinol.Metab 96, E1709-E1718 * equal contribution

Gaston-Massuet, C*., Andoniadou, C. L*., Signore, M., Jayakody, S. A., Charolidi, N., Kyeyune, R., Vernay, B., Jacques, T. S., Taketo, M. M., Le Tissier, P., Dattani, M. T., and Martinez-Barbera, J. P. (2011) Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc Natl Acad Sci USA 2011 July 108, 11482-11487* equal contribution.

Sottocornola, R., Royer, C., Vives, V., Tordella, L., Zhong, S., Wang, Y., Ratnayaka, I., Shipman, M., Cheung, A., Gaston-Massuet, C., Ferretti, P., Molnar, Z., and Lu, X. (2010) ASPP2 binds Par-3 and controls the polarity and proliferation of neural progenitors during CNS development. Dev.Cell 19, 126-137

Gaston-Massuet, C., Kelberman, D., Dattani, M., and Martinez-Barbera, J. P. (2009) Absence of SIX3 mutations in patients with congenital hypopituitarism. Am.J.Med.Genet.A 149A, 2874-2876 

Sajedi, E., Gaston-Massuet, C., Signore, M., Andoniadou, C. L., Kelberman, D., Castro, S., Etchevers, H. C., Gerrelli, D., Dattani, M. T., and Martinez-Barbera, J. P. (2008) Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Dis.Model.Mech. 1, 241-254

Sajedi, E., Gaston-Massuet, C., Andoniadou, C. L., Signore, M., Hurd, P. J., Dattani, M., and Martinez-Barbera, J. P. (2008) DNMT1 interacts with the developmental transcriptional repressor HESX1. Biochimica et biophysica acta 1783, 131-143

Ybot-Gonzalez, P., Gaston-Massuet, C., Girdler, G., Klingensmith, J., Arkell, R., Greene, N. D., and Copp, A. J. (2007) Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling. Development 134, 3203-3211

Andoniadou, C. L., Signore, M., Sajedi, E., Gaston-Massuet, C., Kelberman, D., Burns, A. J., Itasaki, N., Dattani, M., and Martinez-Barbera, J. P. (2007) Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development 134, 1499-1508

Andoniadou, C. L., Signore, M., Young, R. M., Gaston-Massuet, C., Wilson, S. W., Fuchs, E., and Martinez-Barbera, J. P. (2011) HESX1- and TCF3-mediated repression of Wnt/beta-catenin targets is required for normal development of the anterior forebrain. Development 138, 4931-4942 

Gaston-Massuet, C., Henderson, D. J., Greene, N. D., and Copp, A. J. (2005) Zic4, a zinc-finger transcription factor, is expressed in the developing mouse nervous system. Dev.Dyn. 233, 1110-1115 

Murdoch, J. N., Henderson, D. J., Doudney, K., Gaston-Massuet, C., Phillips, H. M., Paternotte, C., Arkell, R., Stanier, P., and Copp, A. J. (2003) Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse. Hum.Mol.Genet. 12, 87-98

* Equal contribution 

Awards and Prizes

Research

2014 - British Society of Paediatric Endocrinology Research Award: Targeting prostaglandins EP-receptors in craniopharyngioma

2014 - Barts & The London Cancer Charity: (£8000) Chemoprotective effect of Cox2-Selective NSAIDs       

2013 - Outstanding research abstract, American Endocrinology Society Annual Meeting, San Francisco

2013 - Society for Endocrinology Young Endocrinologist Basic Science Prize

2013 - Early Career Grant, Society for Endocrinology

2012 - Best poster of the European Society of Endocrinology, Florence

2011 - Outstanding research abstract from the American Endocrinology Society Annual Meeting, Boston

2010 - Best basic science abstract award from the British Society of Paediatric Endocrinology. 

2010 - Henning Anderson Prize for best basic science from European Society of Endocrinology

2004 - UCL PhD poster competition prize

2000 - British Heart Foundation PhD Scholarship

1997 - Barcelona University Exchange Programme Scholarship to study at King’s College

Others

2011 - Endo Boston 2011 travel award to attend to annual American Endo Society meeting 

2003 - Brain travel award to attend a scientific meeting

2001 - Brain travel award to attend a scientific meeting

Book chapters 

Yearbook of Paediatric Endocrinology, 2015, Pituitary & Neuroendocrinology , KARGER. Carles Gaston-Massuet, Nicolas de Roux E. Gevers

Yearbook of Paediatric Endocrinology, 2014, Pituitary & Neuroendocrinology , KARGER. E. Gevers*, Carles Gaston-Massuet* & Nicolas de Roux

Yearbook of Paediatric Endocrinology, 2013, Pituitary. KARGER. E. Gevers, C.Gaston-Massuet & Mehul Dattani

Yearbook of Paediatric Endocrinology, 2012, Pituitary. KARGER. Evelien Gevers, Carles Gaston-Massuet & Mehul Dattani

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