Where Ideas grow

Cancer Signalling & Metabolism

ABOUT

The group aims to identify molecular mechanisms involved in human cancer development with potential applications in the diagnosis, prognosis and targeted therapy, using as models thyroid and other neuroendocrine tumors. Besides the component of translational research, the group has basic research interests such as oncogenic signaling, survival mechanisms and mechanisms/molecules involved in mobility and invasion. Within this frame, a particular attention is paid to: a) signalling induced by genetic alterations in tyrosine kinase receptors and signal transducing molecules involved in the MAPK  and the PI3K/mTOR pathway; b) survival mechanisms of cancer cells, including telomerase reactivation and apoptosis dysregulation; c) molecular mechanisms of metabolic alterations secondary to mitochondrial DNA mutations/deletions or to mutations in nuclear genes encoding metabolic enzymes.

RESEARCH

In 2003, we identified BRAFV600E mutation as a major oncogenic event in papillary thyroid carcinoma. Since then the group has been focusing on the genetic alterations underlying genotypic-phenotypic correlations and in the signaling of oncogenic activation in thyroid tumors. This line of research is still being pursued through the study of thyroid tumors as well as other tumor types characterized by a high prevalence of BRAF mutations (nevi and melanoma), using in vitro and in vivo models to progress in the understanding of the BRAF-induced cellular effects. We also addressed the etiopathogenesis of familial forms of thyroid cancer, namely medullary thyroid carcinoma. In close collaboration with clinicians we have been collecting families with thyroid cancer aggregation. Regarding the effect of environmental factors in thyroid carcinogenesis we have been following-up a cohort of individuals that suffered, 50 to 60 years ago, epilation by scalp X-ray irradiation for Tinea capitis treatment. We verified that mtDNA large deletions are a hallmark of Hurthle cell tumours. The results obtained in the field of mitochondrion-rich tumors were the starting point for the study of mitochondrial and metabolic dysfunction in cancer, a sub-area in which our group is using several models other than thyroid tumors.

One of our group interests is to understand telomere maintenance mechanisms. We have unveiled TERT promoter mutations in thyroid cancer as a mechanism for telomere elongation. In the figure, we present interphase and metaphase spreads (blue) of a thyroid cancer cell line, K1, where we can observe by

Team Coordinators

Team

Selected Publications

Soares P., Trovisco V., Rocha A.S., Lima J., Castro P., Preto A., Máximo V., Botelho T., Seruca R., Sobrinho-Simões M.,
BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene22(29):4578-4580, 2003. [Journal: Article] [CI: 522] [IF: 6,5]
DOI: 10.1038/sj.onc.1206706 SCOPUS: 0043170833. .

Correia M., Pinheiro P., Batista R., Soares P., Sobrinho-Simões M., Máximo V.,
Etiopathogenesis of oncocytomas. Seminars in Cancer Biology47:82-94, 2017. [Journal: Review] [CI: 5] [IF: 10,2]
DOI: 10.1016/j.semcancer.2017.06.014 SCOPUS: 85023602451. .

Vinagre J., Almeida A., Pópulo H., Batista R., Lyra J., Pinto V., Coelho R., Celestino R., Prazeres H., Lima L., Melo M., Rocha A.G.D., Preto A., Castro P., Castro L., Pardal F., Lopes J.M., Santos L.L., Reis R.M., Cameselle-Teijeiro J., Sobrinho-Simões M., Lima J., Máximo V., Soares P.,
Frequency of TERT promoter mutations in human cancers. Nature Communications4:, 2013. [Journal: Article] [CI: 482] [IF: 10,7]
DOI: 10.1038/ncomms3185 SCOPUS: 84884524540. .

Boaventura P., Soares P., Pereira D., Teixeira-Gomes J., Sobrinho-Simões M.,
Head and neck lesions in a cohort irradiated in childhood for tinea capitis treatment. The Lancet Infectious Diseases11(3):163-164, 2011. [Journal: Letter] [CI: 14] [IF: 17,4]
DOI: 10.1016/S1473-3099(11)70047-0 SCOPUS: 79952026090. .

Nunes J.B., Peixoto J., Soares P., Maximo V., Carvalho S., Pinho S.S., Vieira A.F., Paredes J., Rego A.C., Ferreira I.L., Gomez-Lazaro M., Sobrinho-Simoes M., Singh K.K., Lima J.,
OXPHOS dysfunction regulates integrin-ß1 modifications and enhances cell motility and migration. Human Molecular Genetics24(7):1977-1990, 2014. [Journal: Article] [CI: 21] [IF: 6,4]
DOI: 10.1093/hmg/ddu612 SCOPUS: 84926488610. .

Couto J.P., Daly L., Almeida A., Knauf J.A., Fagin J.A., Sobrinho-Simões M., Lima J., Máximo V., Soares P., Lyden D., Bromberg J.F.,
STAT3 negatively regulates thyroid tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America109(35):E2361-E2370, 2012. [Journal: Article] [CI: 95] [IF: 9,7]
DOI: 10.1073/pnas.1201232109 SCOPUS: 84871862427. .

Pópulo H., Boaventura P., Vinagre J., Batista R., Mendes A., Caldas R., Pardal J., Azevedo F., Honavar M., Guimarães I., Manuel Lopes J., Sobrinho-Simões M., Soares P.,
TERT promoter mutations in skin cancer: The effects of sun exposure and X-irradiation. Journal of Investigative Dermatology134(8):2251-2257, 2014. [Journal: Article] [CI: 71] [IF: 7,2]
DOI: 10.1038/jid.2014.163 SCOPUS: 84904458479. .

Rindi G., Klöppel G., Couvelard A., Komminoth P., Körner M., Lopes J.M., McNicol A.M., Nilsson O., Perren A., Scarpa A., Scoazec J.Y., Wiedenmann B.,
TNM staging of midgut and hindgut (neuro) endocrine tumors: A consensus proposal including a grading system. Virchows Archiv451(4):757-762, 2007. [Journal: Article] [CI: 708] [IF: 2]
DOI: 10.1007/s00428-007-0452-1 SCOPUS: 34848828173. .

Batista R., Cruvinel-Carloni A., Vinagre J., Peixoto J., Catarino T.A., Campanella N.C., Menezes W., Becker A.P., De Almeida G.C., Matsushita M.M., Clara C., Neder L., Viana-Pereira M., Honavar M., Castro L., Lopes J.M., Carvalho B., Vaz R.M., Máximo V., Soares P., Sobrinho-Simões M., Reis R.M., Lima J.,
The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism. International Journal of Cancer139(2):414-423, 2016. [Journal: Article] [CI: 32] [IF: 6,5]
DOI: 10.1002/ijc.30057 SCOPUS: 84961644849. .

Faustino A., Couto J.P., Pópulo H., Rocha A.S., Pardal F., Cameselle-Teijeiro J.M., Lopes J.M., Sobrinho-Simões M., Soares P.,
mTOR pathway overactivation in BRAF mutated papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism97(7):, 2012. [Journal: Article] [CI: 59] [IF: 6,4]
DOI: 10.1210/jc.2011-2748 SCOPUS: 84863566153. .

Ongoing Projects

Tackling cancer stem cells: a challenge and an opportunity to advance in anti-cancer therapy (CANCERSTEM)
Reference: POCI-01-0145-FEDER-016390
Proponent: Ipatimup
Sponsor: FCT
From 01-JAN-17 to 30-JUN-21
Estudo clínico, patológico e molecular para otimizar o tratamento do carcinoma diferenciado da tiroide.
Reference: IBECATI
Proponent: Ipatimup
Sponsor: SPEDM
From 12-APR-17 to 31-DEC-23
ROle of the MITOchondrial fission protein Drp1 as a prognosis and predictive biomarker in the treatment of differentiated thyroid cancer (ROMITO-DRP1)
Reference: ROMITO-DRP1
Proponent: Ipatimup
Sponsor: EISAI
From 01-MAY-17 to 30-APR-22
LIPOPREDICT: Previsão da resposta dos pacientes a fármacos antineoplásicos lipossomais: focando na atividade endocítica do LRP1B
Reference: POCI-01-0145-FEDER-031520
Proponent: Ipatimup
Sponsor: FCT
From 15-JUL-18 to 14-JAN-22
As outras faces da Telomerase: olhando para além da imortalização tumoral
Reference: POCI-01-0145-FEDER-031438
Proponent: Ipatimup
Sponsor: FCT
From 26-JUL-18 to 25-JAN-22
The other faces of telomerase in thyroid cancer: looking beyond tumour immortalization
Proponent: Ipatimup
Sponsor: SPEDM
From 01-OCT-18 to 30-SEP-23
Implementação de Biomarcadores Moleculares para medicina de precisão com doentes com tumores cerebrais pediátricos
Reference: LEOJL
Proponent: Ipatimup
Sponsor: Liga Portuguesa Contra o Cancro
From 04-SEP-18 to 03-SEP-21
Bases moleculares para o diagnóstico precoce e tratamento de tumores adrenocorticals na era da medicina personalizada
Reference: PTDC/MEC-ONC/31384/2017
Proponent: Ipatimup
Sponsor: FCT
From 01-OCT-18 to 30-SEP-22
Development of a biomimetic multifunctional pré-clinical model to assist immunotherapy optimization.
Reference: IMUNOMIMETIC
Proponent: Ipatimup
Sponsor: Astrazeneca
From 18-DEC-18 to 31-DEC-22
Estudo das possíveis interações entre a mutação BRAFV600E e a via do mTOR em carcinomas papilares da tiroide: potenciais consequências no comportamento tumoral e na resposta à terapia
Proponent: Ipatimup
Sponsor: SPEDM
From 01-APR-19 to 30-MAR-23
Is thyroid gland a target of SARS-CoV-2 infection? Early identification and follow-up of thyroid dysfunction in COVID-19 patients
Reference: Proj.n? 625
Proponent: Ipatimup
Sponsor: FCT
From 09-JUL-20 to 09-JUN-21
Molecular subtypes switching in non-invasive and muscle-invasive bladder cancer – the emerging role of biomarker
Proponent: Ipatimup
Sponsor: Roche
From 27-AUG-20 to 26-AUG-23
Targeting mitochondrial TERT to overcome therapeutic resistance
Proponent: Ipatimup
Sponsor: ETA
From 15-JUL-20 to 14-JUL-23
Diabetes mellitus and oncocytic tumors of thyroid: the mitochondrial connection.
Reference: MITODI
Proponent: Ipatimup
Sponsor: SPEDM
From 01-JUN-20 to 31-DEC-22