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Cancer Signalling Laboratory

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Cancer Signalling Laboratory


About the CSL

The Cancer Signalling Laboratory (CSL) investigates the role of FOXO transcription factors in cancer, metabolism and aging. We have discovered the FOXO repressor protein TRIB2 as a novel oncogene in melanoma which confers resistance to anticancer drugs. In addition, we are developing FOXO activation compounds and nuclear export inhibitors as anti-cancer drug candidates.


Publications (2008-2017)

Link W. and Fernandez-Marcos P. (2017) FOXO transcription factors at the interface of metabolism and cancer. International Journal of Cancer doi: 10.1002/ijc.30840.

Link W. (2017) Mind the gap, see the immuno-connection. Nature Chem. Biol. Apr 24. doi: 10.1038/nchembio.2373.

Hill R., Madureira PA, Ferreira, B, Baptista. I, Machado, S, Colaço L., dos Santos M.,  Liu N., Dopazo, A, Ugurel S., Adrienn A., Kiss-Toth E., Isbilen M., Gure AO and Link W. (2017) TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT. Nature Comm. 8, 14687. doi: 10.1038/ncomms14687.

Ferreira BI, Lie MK, Engelsen AST, Machado S, Link W and James B. Lorens (2017) Adaptive mechanisms of resistance to antineoplastic agents. MedChemComm, 8, 53 – 66.

Cautien B., Castillo F, Musso L, de Pedro N, Rodriguez Quesada L, Vicente Pérez F, Dallavalle S and Link W. (2016) Discovery of a novel, specific isothiazolonaphthoquinone-based small molecule activator of FOXO nuclear-cytoplasmic shuttling. PLoS One 11(12):e0167491. doi: 10.1371/journal.pone.0167491.

Florindo, C, Ferreira BI, Serrão SM, Tavares, AA, Hill R, and Link W. (2016) Subcellular protein localization in health and disease. eLS. John Wiley & Sons, Ltd: Chichester DOI: 10.1002/9780470015902.a0026534.

Martins R., Lithgow G.J., Link W. (2016) Long live FOXO: Unravelling the role of FOXO proteins in aging and longevity. Aging Cell 15, 196-207. doi: 10.1111/acel.12427.

Lerin C, Goldfine AB, Boes T, Liu M, Kasif S, Dreyfuss JM, De Sousa-Coelho AL, Daher G, Manoli I, Sysol JR, Isganaitis E, Jessen N, Goodyear LJ, Beebe K, Gall W, Venditti CP, Patti ME. (2016). Defects in muscle branched-chain amino acid oxidation contribute to impaired lipid metabolism. Mol Metab. 5(10):926-36.

Makimura H, Stanley TL, Suresh C, De Sousa-Coelho AL, Frontera WR, Syu S, Braun LR,  Looby SE, Feldpausch MN, Torriani M, Lee H, Patti ME, Grinspoon SK. (2016). Metabolic Effects of Long-Term Reduction in Free Fatty Acids With Acipimox in Obesity: A Randomized Trial. J Clin Endocrinol Metab. 101(3):1123-33.

Ferreira BI, Hill R, and Link W. (2015) Caught in the crosshairs; targeted drugs and personalized medicine. Cancer J. 21, 441-447. doi: 10.1097/PPO.0000000000000161.

Link W. (2015) Tribbles breaking bad: TRIB2 suppresses FOXO and acts as an oncogenic protein in melanoma. Biochemical Society Transactions 43, 1085-1088; DOI: 10.1042/BST20150102.

Castellarnau M., Zanuy M., Cortés R., Tarragó-Celada J., Fan T.W., Link W. and Cascante M. (2015) FOXO3a mediates the antitumour effects of methylseleninic acid. Pharmacol Res. 102, 218-234.

Hill R., Kalathur R., Colaço L., Brandão R., Ugurel S., Futschik M. and Link W. (2015) TRIB2 as a biomarker for diagnosis and progression of melanoma. Carcinogenesis 36, 469-477.

Link W. (2015) Molecular Inhibitors in Targeted Therapy. Molecular inhibitors in targeted therapy. Volume 1, Issue 1, ISSN (Online) 2300-3650, DOI: 10.1515/motth-2015-0001.

Cautien B., de Pedro N., Reyes F. and Link W. (2015) Image-based Identification of Nuclear Export Inhibitors from Natural Products. Methods in Molecular Biology 1270:307-19. doi: 10.1007/978-1-4939-2309-0_22.

Cautien B., Hill R., de Pedro N. and Link W.  (2015) Components and regulation of nuclear transport processes. FEBS J. 282, 445-462. This article is accompanied by a podcast (

Castillo Correa, F. J. ,De Pedro, N. ,Rodriguez Quesada, L. ,Oves Costales, D. ,Tormo, J. R. ,Martin, J., Reyes, F. ,Genilloud, O. ,Vicente, F. ,Link, W. ,Cautain, B.  (2014) Discovery of novel inhibitor of FOXO nuclear-cytoplasmic shuttling from natural products of marine origin. European Journal of Cancer, 50, 24.

Hill R., Kalathur R., Callejas S., Colaço L., Brandão R., Garcia Serelde B., Cebriá A., Blanco-Aparicio C., Pastor J., Futschik M., Dopazo A. and Link W. (2014) Gemone wide expression profiling in breast cancer following Phosphatidylinositol 3-Kinase (PI3K) inhibition directs p53-independent cell cycle arrest via the differential induction of FOXO-dependent genes. Breast Cancer Research 16, 482.

Mori M, Vignaroli G, Cau, Y, Dinić J, Hill R, Rossi M, Colecchia D, Pešić M, Link W, Chiariello M, Ottmannh C and Botta M. (2014) Discovery of 14-3-3 protein-protein interaction inhibitors that sensitize multidrug resistant cancer cells to Doxorubicin and the Akt inhibitor GSK690693. ChemMedChem 9, 973-983.

Cortés R., Tarrado M., Talancón D., López, C., Link W., Daniel Ruiz D., Centelles J.J., Quirantee J. and Cascante M. (2014) A novel cyclometallated Pt(II)-ferrocene complex induces nuclear FOXO3a localization, apoptosis and synergizes with cisplatin to inhibit lung cancer cell proliferation. Metallomics 6, 622-633.

Hill R., Cautien B., de Pedro N. and Link W. (2014) Targeting Nucleocytoplasmic Transport in Cancer Therapy. Oncotarget 5, 11-28.

Cautien B., de Pedro N.  Muñoz de Escalona M., González Menéndez V., Tormo  J.R., Martin J., El Aouad N., Reyes F., Asensio F., Genilloud O., Vicente Pérez F. and Link W.(2014) High-content screening of natural products reveals novel nuclear export inhibitors. Journal of Biomolecular Screening 19, 57-65.

Link W., Madureira PA and Hill R. (2013) Identifying new targets for personalized medicine. eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0024865.

Evensen L., Link W. and Lorens J.B. (2013) Image-based high-throughput screening for inhibitors of angiogenesis. Methods Mol Biol. 931, 139-151.

Zanella F., Dos Santos NR and Link W. (2013) Moving to the Core: Spatiotemporal Analysis of Forkhead box O (FOXO) and Nuclear factor-κB (NF-κB) nuclear translocation. Traffic 14, 247-258.

Granda T.G., Cebrián D., Martínez S., Anguita P.V., López E.C., Link W., Merino T., Pastor J., Serelde B.G., Peregrina S., Palacios I., Albarran M.I., Cebriá A., Lorenzo M., Alonso P., Fominaya J., López A.R. and Bischoff JR (2013) Biological characterization of ETP-46321 a selective and efficacious inhibitor of phosphoinositide-3-kinases. Invest New Drugs 31, 66-76.

Link W. Nuclear accumulation of β-catenin and forkhead box O3a in colon cancer: Dangerous liaison (2012) World J Biol Chem. 26, 175-179.

Martínez González S., Hernández A.I., Varela C., Lorenzo M., Ramos-Lima F., Cendón E., Cebrián D., Aguirre E., Gomez-Casero E., Albarrán M.I., Alfonso P., García-Serelde B., Mateos G., Oyarzabal J., Rabal O., Mulero F., Gonzalez-Granda T., Link W., Fominaya J., Barbacid M., Bischoff JR., Pizcueta P. Blanco-Aparicio C. and Pastor J. (2012) Rapid identification of ETP-46992, orally bioavailable PI3K inhibitor, selective versus mTOR. Bioorg Med Chem Lett 22, 5208-5214.

Martínez González S., Hernández A.I., Varela C., Rodríguez-Arístegui S., Lorenzo M., Rodríguez A., Rivero V., Martín J.I., Saluste C.G., Ramos-Lima F., Cendón E., Cebrián D., Aguirre E., Gomez-Casero E., Albarrán M., Alfonso P., García-Serelde B., Oyarzabal J., Rabal O., Mulero F., Gonzalez-Granda T., Link W., Fominaya J., Barbacid M., Bischoff JR., Pizcueta P. and Pastor J. (2012) Identification of ETP-46321, a potent and orally bioavailable PI3K α, δ inhibitor. Bioorg Med Chem Lett. 22, 3460-3466.

Martínez González S., Hernández A.I., Varela C., Rodríguez-Arístegui S., Alvarez R.M., García A.B., Lorenzo M., Rivero V., Oyarzabal J., Rabal O., Bischoff J.R., Albarrán M., Cebriá A., Alfonso P., Link W., Fominaya J. and Pastor J. (2012) Imidazo[1,2-a]pyrazines as Novel PI3K Inhibitors, Bioorg Med Chem Lett. 22, 1874-1878.

Kauselmann G., Dopazo A., and Link W. (2012) Identification of disease-relevant genes for molecularly targeted drug discovery. Current Cancer Drug Targets, 1, 1-13.

Hung M.C. and Link W. (2011) Protein localization in disease and therapy. Journal Cell Science 124, 3381–3392.

Link W. (2011) Context–dependent therapeutic potential of FOXO proteins in oral squamous cell carcinoma. Oral Oncology 47, 229-230.

Link W. (2011) FOXO proteins as potential targets for anticancer therapy. Current Drug Targets 12, 1232-1234.

Evensen L., Link W. and Lorens J.B. (2010) Imaged-based high-throughput screening for anti-angiogenic drug discovery. Current Pharmaceutical Design, 16(35):3958-63.

Zanella F., Lorens JB and Link W. (2010) High Content Screening – Seeing is Believing. Trends Biotechnol. 28, 237-245. (Title story + Cover art).

Zanella F., Renner O., García B., Callejas S., Dopazo A., Peregrina S., Carnero A. and Link W. (2010) Human TRIB2 is a repressor of FOXO that contributes to the malignant phenotype of melanoma cells. Oncogene 29, 2973-2982.

Rabal O., Link W., García B, Bischoff J.R. and  Oyarzabal J. (2010) An integrated one step system to extract, analyze and annotate all relevant information from image-based cell screening of chemical libraries. Mol. Biosyst., 6, 711 – 720.

Zanella F., Link W., Carnero A. (2010) Understanding FOXO, new views on old transcription factors. Curr Cancer Drug Targets 10, 135-146.

Evensen L., Micklem D.R., Link W. and Lorens JB (2010). A Novel Imaging-Based High-Throughput Screening Approach to Anti-Angiogenic Therapeutic Discovery. Cytometry A 77, 41-51.

Link W., Oyarzabal J., Serrelde BG., Albarran MI, Rabal O., Cebriá A, Alfonso P, Fominaya J, Renner O, Peregrino S, Soilán D, Ceballos PA, Hernández AI, Lorenzo L, Pevarello P, Gonzalez-Granda T, Kurz G, Carnero A. and Bischoff J.R. (2009). Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J Biol Chem 284, 28392-28400.

Zanella F., Rosado A., García, G., Carnero A. and Link W(2009). Using multiplexed regulation of luciferase activity and GFP translocation to screen for FOXO modulators. BMC Cell Biol. 10, 14.

Zanella F., Rosado A., García, G., Blanco F, Carnero A. and Link W(2008).  Chemical genetic analysis of FOXO nuclear-cytoplasmic shuttling using Image-Based Cell Screening. ChemBioChem, 9, 2229-2237.

Rosado A., Zanella F., Garcia B., Carnero A. and Link W(2008) A Dual-Color Fluorescence-Based Platform to Identify Selective Inhibitors of Akt Signaling. PLoS ONE3(3), e1823.

Carnero A., Blanco-Aparicio C., Renner O. Link W. and Leal, J.F.M (2008). The PTEN/PI3K/AKT Signaling Pathway in Cancer, therapeutic Implications. Curr. Cancer Drug Targets. 8, 187-198.


Other Publications

Link W. (2010) Finding novel targets for anticancer therapy. European Pharmaceutical Review, 2, 27- 29.

Carrión A.M., Taylor J.S., Link W., Morcuende S., Mellström B. and Naranjo, J.R. (1996) Early gene induction and spinal cord function. Dolor 11, 22-24

Books Chapters

Link W. Anti-cancer drugs – discovery, development and therapy. (2015) International Manual of Oncology Practice ISBN 978-3-319-21683-6

Carnero A., Blanco C., Blanco F, Castro M. E., Guijarro M.V., Fominaya J., Link W., Martínez J.F., Moneo V., Renner O.,  Romero L. and Rosado A (2003) Exploring cellular senescence as a tumor suppressor mechanism. Rev. Oncol. 5, 249-265.



Hill R. and Link W. (2015) on components and regulation of nuclear transport processes. FEBS J.


Project Grants


Project Leader

2014-2015 LC2014-017: “Impact of FOXO activators on aging” The Longevity Consortium, Wolfgang Link and Gordon J. Lithgow (Buck Institute for Research on Aging, SF, USA)

2013 – 2014 2012-08-0765: “The role of tribbles homolog 2 (TRIB2) in drug resistance” Bayer Pharma AG

BIO2006-02432 (Spanish MEC) (2006 – 2009) Targeting the PI3K/Akt signaling pathway:  Identification of lead compounds and therapeutic targets.

BIO2002-00197 (Spanish MCyT) (2002 – 2005) Development of technologyplatforms to monitor the PI3K/Akt sgnaling pathway for anticancer drug discovery.



Inventors: Pastor J. F., Kurz, G., Rico Ferreira M.D.R, Soilan Rodriguez, D., Ortega Soret M.A., Link W., Rabal O. and Garcia O. (2011) Title: New amino-imidazolothiadiazole compound useful for treating e.g. cancer, cardiovascular disease, viral infection, inflammation, neurological disorder, bone disorder, atherosclerosis, pulmonary fibrosis, restenosis, stroke, diabetes Patent Number: WO2012020215-A1

Inventors: Hoener, M., Link, W., Cassata, G., Baumeister, R., Tovar, K. (2001) Title: Caenorhabditis parkin gene and transgenic nematodes for use as Parkinson’s disease models and for drug screening Patent Number: WO 2001070944

Inventors: Naranjo, J.R., Mellström, B., Dompablo Garcia, I., Link, W., Carrión, A.M., Ledo, F. (2000) Title: Calcium-dependent transcriptional regulator DREAM and its cDNA and methods for drug screening. Patent Number: WO2000037498


Funded Research Projects

2017/2019 – RED transfronteriza para el desarrollo de productos innovadores con microALGAs (ALGARED+), Programa Cooperación Transforiza Espanha Portugal (POCTEP), Principal Investigator: Rosa León Bañares.

2017/2018 – Terry Fox Prize, Liga Portuguesa Contra o Cancro, Principal Investigator: Bibiana Ferreira.

2016/2017 – Characterization of TRIB2-mediated resistance to anti-melanoma drugs, LPCC-NRS/TERRY FOX, Principal Investigator: Wolfgang Link.

2016/2017- Terry Fox Prize, Liga Portuguesa Contra o Cancro, Principal Investigator: Wolfgang Link.

2016/2017- Santander Research Mobility Award, Banco Santander, Principal Investigators: Endre Kiss-Toth, Guillermo Velasco, Wolfgang Link.

2015/2016- Laço Prize, Associação Laço, Principal Investigator: Wolfgang Link. 

2014/2015 – Impact of FOXO activators on aging, The National Institute on Aging Longevity Consortium, Principal Investigator: Wolfgang Link and Gordon J. Lithgow (Buck Institute for Research on Aging, SF, USA).

2013/2014 – The role of tribbles homolog 2 (TRIB2) in drug resistance, Bayer Pharma AG, Principal Investigator: Wolfgang Link.

2006/2009 – Identificación de compuestos líder y dianas terapéuticas: Utilización de la vía de PI3K/Akt para el descubrimiento de compuestos anticancerígenos, Ministerio de Ciencia y Educación (Spain), Principal Investigator: Wolfgang Link.





Representative Images