CANCER EPIGENOMICS UNIT

genomica-icon_1

Epigenomics is a new and growing field of ??interest that is helping to answer many unsolved questions in the field of Oncology. The Cancer Epigenomics Unit, led by Dr. Angel Díaz-Lagares, is interested on the identification and clinical evaluation of new epigenetic biomarkers for diagnosis, prognosis and therapy response to achieve precision oncology.

To reach this purpose we analyze tumor and liquid biopsy samples from cancer patients using epigenetic and epigenomic approaches. Moreover, we are interested in the epigenomic characterization of tumors in order to increase the knowledge of the epigenetic mechanisms responsible for the development and progression of this disease.

Technological capacities


For epigenomic studies we have the most innovative technology in this field based especially on next generation sequencing (NGS) and microarray systems:

  • Next generation sequencing using NextSeq500 (Illumina), for partial or complete analysis of the genome and epigenome.
  • HiScan microarray system (Illumina), which allows the analysis of DNA methylation microarrays with more than 850,000 CpGs.
  • Pyrosequencing with PyroMark Q24 (Qiagen), for sequencing and quantitative analysis of DNA methylation.
  • Real-time PCR using the StepOne system (Applied Biosystems), which allows sensitive quantification of DNA methylation.
  • Access to the digital PCR System QX200 (Biorad) of the Liquid Biopsy Unit (Oncomet group), which enables ultrasensitive detection and quantification of DNA methylation.

Research lines


  • Identification and clinical evaluation of epigenetic biomarkers by analyzing circulating tumor DNA and circulating tumor cells (CTCs) in liquid biopsy samples for precision oncology.
  • Development and validation of new diagnostic tools and epigenetic biomarkers in oncology.
  • Epigenomic characterization of tumors based on microarray techniques and next generation sequencing (NGS).
  • Epigenetic analysis of long non-coding RNAs (lncRNAs) and their clinical implications in cancer.

Equipo


Ángel Díaz-Lagares
Principal investigator
Aitor Casanova Rodriguez
PhD Student
Nicolás Costa Fraga
PhD Student
Aida Bao Caamaño
PhD Student
Clara Castro Carballeira
Degree Final Project (TFG) Student

Development of an epigenetic signature in liquid biopsy to predict therapy response in mestastatic colorectal cancer. ISCIII (PI18/00307). 2019-2021.

Identification of epigenetic biomarkers in liquid biopsy for precisión oncology in advanced breast cancer. FSEOM/FECMA. 2018-2019.

Clinical validation of the EPiGen kit: A new test to predict the response to Non-Small Cell Lung Cancer (NSCLC). EPIGEN-KIT. MINECO. RTC-2016-5314-1. 2017-2019.

Epigenomic characterization of ciruclating tumor cells (CTCs) in colon cancer. Crowdfunding. 2018-2020.

Clinical evaluation of methylation of long non-coding RNAs (lncRNAs) genes in tumors and liquid biopsy as biomarkers in colorectal cancer. Crowdfunding. 2018-2020.

 

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Diaz-Lagares A, Crujeiras AB, Lopez-Serra P, Soler M, Setien F, Goyal A, Sandoval J, Hashimoto Y, Martinez-Cardús A, Gomez A, Heyn H, Moutinho C, Espada J, Vidal A, Paúles M, Galán M, Sala N, Akiyama Y, Martínez-Iniesta M, Farré L, Villanueva A, Gross M, Diederichs S, Guil S, Esteller M. PNAS. 2016 Nov 22;113(47):E7535-E7544.

A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer. Diaz-Lagares A, Mendez-Gonzalez J, Hervas D, Saigi M, Pajares MJ, Garcia D, Crujerias AB, Pio R, Montuenga LM, Zulueta J, Nadal E, Rosell A, Esteller M, Sandoval J. Clinical Cancer Research. 2016 Jul 1;22(13):3361-71. doi: 10.1158/1078-0432.CCR-15-2346.

Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Moran S, Martínez-Cardús A, Sayols S, Musulén E, Balañá C, Estival-Gonzalez A, Moutinho C, Heyn H,Diaz-Lagares A, de Moura MC, Stella GM, Comoglio PM, Ruiz-Miró M, Matias-Guiu X, Pazo-Cid R, Antón A, Lopez-Lopez R, Soler G, Longo F, Guerra I, Fernandez S, Assenov Y, Plass C, Morales R, Carles J, Bowtell D, Mileshkin L, Sia D, Tothill R, Tabernero J, Llovet JM, Esteller M. Lancet Oncol. 2016 Oct;17(10):1386-1395. doi: 10.1016/S1470-2045(16)30297-2. Epub 2016 Aug 27.

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. Léveillé N, Melo CA, Rooijers K, Díaz-Lagares A, Melo SA, Korkmaz G, Lopes R, Akbari Moqadam F, Maia AR, Wijchers PJ, Geeven G, den Boer ML, Kalluri R, de Laat W, Esteller M, Agami R. Nature Communications. 2015 Mar 27;6:6520. doi: 10.1038/ncomms7520.

Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. Crujeiras AB, Morcillo S, Diaz-Lagares A, Sandoval J, Castellano-Castillo D, Torres E, Hervas D, Moran S, Esteller M, Macias-Gonzalez M, Casanueva FF, Tinahones FJ. Int J Obes (Lond). 2018 May 1. doi: 10.1038/s41366-018-0065-6. PMID: 29717273

An Epigenetic Signature in Adipose Tissue Is Linked to Nicotinamide N-Methyltransferase Gene Expression. Crujeiras AB, Pissios P, Moreno-Navarrete JM, Diaz-Lagares A, Sandoval J, Gomez A, Ricart W, Esteller M, Casanueva FF, Fernandez-Real JM. Mol Nutr Food Res. 2018 Apr 24:e1700933. doi: 10.1002/mnfr.201700933. PMID: 29688621

Epigenomic signature of adrenoleukodystrophy predicts compromised oligodendrocyte differentiation. Schlüter A, Sandoval J, Fourcade S, Díaz-Lagares A, Ruiz M, Casaccia P, Esteller M, Pujol A. Brain Pathol. 2018 Feb 24. doi: 10.1111/bpa.12595. PMID: 29476661

Liquid Biopsy: From Basic Research to Clinical Practice. Macías M, Alegre E, Díaz-Lagares A, Patiño A, Pérez-Gracia JL, Sanmamed M, López-López R, Varo N, González A. Adv Clin Chem. 2018;83:73-119. doi: 10.1016/bs.acc.2017.10.003. PMID: 29304904

CD137 (4-1BB) Costimulation Modifies DNA Methylation in CD8+ T Cell-Relevant Genes. Aznar MA, Labiano S, Diaz-Lagares A, Molina C, Garasa S, Azpilikueta A, Etxeberria I, Sanchez-Paulete AR, Korman AJ, Esteller M, Sandoval J, Melero I. Cancer Immunol Res. 2018 Jan;6(1):69-78. doi: 10.1158/2326-6066.CIR-17-0159. PMID: 29133290

Translating cancer epigenomics into the clinic: focus on lung cancer. Mari-Alexandre J, Diaz-Lagares A, Villalba M, Juan O, Crujeiras AB, Calvo A, Sandoval J. Transl Res. 2017 Nov;189:76-92. doi: 10.1016/j.trsl.2017.05.008. PMID: 28644958

Obesity and menopause modify the epigenomic profile of breast cancer. Crujeiras AB, Diaz-Lagares A, Stefansson OA, Macias-Gonzalez M, Sandoval J, Cueva J, Lopez-Lopez R, Moran S, Jonasson JG, Tryggvadottir L, Olafsdottir E, Tinahones FJ, Carreira MC, Casanueva FF, Esteller M. Endocr Relat Cancer. 2017 Jul;24(7):351-363. doi: 10.1530/ERC-16-0565. PMID: 28442560

DNA methylation map in circulating leukocytes mirrors subcutaneous adipose tissue methylation pattern: a genome-wide analysis from non-obese and obese patients. Crujeiras AB, Diaz-Lagares A, Sandoval J, Milagro FI, Navas-Carretero S, Carreira MC, Gomez A, Hervas D, Monteiro MP, Casanueva FF, Esteller M, Martinez JA. Sci Rep. 2017 Feb 17;7:41903. doi: 10.1038/srep41903. PMID: 28211912

Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Diaz-Lagares A, Crujeiras AB, Lopez-Serra P, Soler M, Setien F, Goyal A, Sandoval J, Hashimoto Y, Martinez-Cardús A, Gomez A, Heyn H, Moutinho C, Espada J, Vidal A, Paúles M, Galán M, Sala N, Akiyama Y, Martínez-Iniesta M, Farré L, Villanueva A, Gross M, Diederichs S, Guil S, Esteller M. Proc Natl Acad Sci U S A. 2016 Nov 22;113(47):E7535-E7544. PMID: 27821766

Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Moran S, Martínez-Cardús A, Sayols S, Musulén E, Balañá C, Estival-Gonzalez A, Moutinho C, Heyn H, Diaz-Lagares A, de Moura MC, Stella GM, Comoglio PM, Ruiz-Miró M, Matias-Guiu X, Pazo-Cid R, Antón A, Lopez-Lopez R, Soler G, Longo F, Guerra I, Fernandez S, Assenov Y, Plass C, Morales R, Carles J, Bowtell D, Mileshkin L, Sia D, Tothill R, Tabernero J, Llovet JM, Esteller M. Lancet Oncol. 2016 Oct;17(10):1386-1395. doi: 10.1016/S1470-2045(16)30297-2. PMID: 27575023

Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects. Crujeiras AB, Diaz-Lagares A, Moreno-Navarrete JM, Sandoval J, Hervas D, Gomez A, Ricart W, Casanueva FF, Esteller M, Fernandez-Real JM. Transl Res. 2016 Dec;178:13-24.e5. doi: 10.1016/j.trsl.2016.07.002. PMID: 27477082

MiR-204 silencing in intraepithelial to invasive cutaneous squamous cell carcinoma progression. Toll A, Salgado R, Espinet B, Díaz-Lagares A, Hernández-Ruiz E, Andrades E, Sandoval J, Esteller M, Pujol RM, Hernández-Muñoz I. Mol Cancer. 2016 Jul 25;15(1):53. doi: 10.1186/s12943-016-0537-z. PMID: 27457246

Epigenetic alterations leading to TMPRSS4 promoter hypomethylation and protein overexpression predict poor prognosis in squamous lung cancer patients. Villalba M, Diaz-Lagares A, Redrado M, de Aberasturi AL, Segura V, Bodegas ME, Pajares MJ, Pio R, Freire J, Gomez-Roman J, Montuenga LM, Esteller M, Sandoval J, Calvo A. Oncotarget. 2016 Apr 19;7(16):22752-69. doi: 10.18632/oncotarget.8045. PMID: 26989022

A Novel Epigenetic Signature for Early Diagnosis in Lung Cancer. Diaz-Lagares A, Mendez-Gonzalez J, Hervas D, Saigi M, Pajares MJ, Garcia D, Crujerias AB, Pio R, Montuenga LM, Zulueta J, Nadal E, Rosell A, Esteller M, Sandoval J. Clin Cancer Res. 2016 Jul 1;22(13):3361-71. doi: 10.1158/1078-0432.CCR-15-2346. PMID: 26842235

MiR-221 promotes stemness of breast cancer cells by targeting DNMT3b. Roscigno G, Quintavalle C, Donnarumma E, Puoti I, Diaz-Lagares A, Iaboni M, Fiore D, Russo V, Todaro M, Romano G, Thomas R, Cortino G, Gaggianesi M, Esteller M, Croce CM, Condorelli G. Oncotarget. 2016 Jan 5;7(1):580-92. doi: 10.18632/oncotarget.5979. PMID: 26556862

Notch1 Pathway Activation Results from the Epigenetic Abrogation of Notch-Related MicroRNAs in Mycosis Fungoides.Gallardo F, Sandoval J, Díaz-Lagares A, Garcia R, D’Altri T, González J, Alegre V, Servitje O, Crujeiras AB, Stefánsson ÓA, Espinet B, Hernández MI, Bellosillo B, Esteller M, Pujol RM, Bigas A, Espinosa L. J Invest Dermatol. 2015 Dec;135(12):3144-3152. doi: 10.1038/jid.2015.328. PMID: 26302069

Genome-Wide DNA Methylation Analysis Identifies Novel Hypomethylated Non-Pericentromeric Genes with Potential Clinical Implications in ICF Syndrome. Simo-Riudalbas L, Diaz-Lagares A, Gatto S, Gagliardi M, Crujeiras AB, Matarazzo MR, Esteller M, Sandoval J. PLoS One. 2015 Jul 10;10(7):e0132517. doi: 10.1371/journal.pone.0132517. ECollection 2015. PMID: 26161907

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. Léveillé N, Melo CA, Rooijers K, Díaz-Lagares A, Melo SA, Korkmaz G, Lopes R, Akbari Moqadam F, Maia AR, Wijchers PJ, Geeven G, den Boer ML, Kalluri R, de Laat W, Esteller M, Agami R. Nat Commun. 2015 Mar 27;6:6520. doi: 10.1038/ncomms7520. PMID: 25813522

MicroRNA expression profiling and DNA methylation signature for deregulated microRNA in cutaneous T-cell lymphoma. Sandoval J, Díaz-Lagares A, Salgado R, Servitje O, Climent F, Ortiz-Romero PL, Pérez-Ferriols A, Garcia-Muret MP, Estrach T, Garcia M, Nonell L, Esteller M, Pujol RM, Espinet B, Gallardo F. J Invest Dermatol. 2015 Apr;135(4):1128-1137. doi: 10.1038/jid.2014.487. PMID: 25405321

Pre-treatment circulating leptin/ghrelin ratio as a non-invasive marker to identify patients likely to regain the lost weight after an energy restriction treatment. Crujeiras AB, Díaz-Lagares A, Abete I, Goyenechea E, Amil M, Martínez JA, Casanueva FF. J Endocrinol Invest. 2014 Feb;37(2):119-26. doi: 10.1007/s40618-013-0004-2. PMID: 24497210

MiR-221/222 target the DNA methyltransferase MGMT in glioma cells. Quintavalle C, Mangani D, Roscigno G, Romano G, Diaz-Lagares A, Iaboni M, Donnarumma E, Fiore D, De Marinis P, Soini Y, Esteller M, Condorelli G. PLoS One. 2013 Sep 19;8(9):e74466. doi: 10.1371/journal.pone.0074466. ECollection 2013. PMID: 24147153

Association of weight regain with specific methylation levels in the NPY and POMC promoters in leukocytes of obese men: a translational study. Crujeiras AB, Campion J, Díaz-Lagares A, Milagro FI, Goyenechea E, Abete I, Casanueva FF, Martínez JA. Regul Pept. 2013 Sep 10;186:1-6. doi: 10.1016/j.regpep.2013.06.012. PMID: 23831408

In vivo identification of an HLA-G complex as ubiquitinated protein circulating in exosomes. Alegre E, Rebmann V, Lemaoult J, Rodriguez C, Horn PA, Díaz-Lagares A, Echeveste JI, González A. Eur J Immunol. 2013 Jul;43(7):1933-9. doi: 10.1002/eji.201343318. Epub 2013 May 17. PMID: 23589311

Oxidative stress associated to dysfunctional adipose tissue: a potential link between obesity, type 2 diabetes mellitus and breast cancer. Crujeiras AB, Díaz-Lagares A, Carreira MC, Amil M, Casanueva FF. Free Radic Res. 2013 Apr;47(4):243-56. doi: 10.3109/10715762.2013.772604. PMID: 23409968

Evaluation of multiple serum markers in advanced melanoma.Díaz-Lagares A, Alegre E, Arroyo A, González-Cao M, Zudaire ME, Viteri S, Martín-Algarra S, González A.Tumour Biol. 2011 Dec;32(6):1155-61. doi: 10.1007/s13277-011-0218-x.PMID: 21858537

Evaluation of HLA-G5 plasmatic levels during pregnancy and relationship with the 14-bp polymorphism. Gonzalez A, Alegre E, Torres MI, Díaz-Lagares A, Lorite P, Palomeque T, Arroyo A. Am J Reprod Immunol. 2010 Nov;64(5):367-74. doi: 10.1111/j.1600-0897.2010.00855.x. PMID: 20482523

Detection of 3-nitrotyrosine-modified human leukocyte antigen-G in biological fluids. Díaz-Lagares A, Alegre E, Gonzalez A. Hum Immunol. 2009 Dec;70(12):976-80. doi: 10.1016/j.humimm.2009.07.018. PMID: 19651177

Tyrosine nitration in the human leucocyte antigen-G-binding domain of the Ig-like transcript 2 protein. Díaz-Lagares A, Alegre E, Arroyo A, Corrales FJ, González A. FEBS J. 2009 Aug;276(15):4233-43. doi: 10.1111/j.1742-4658.2009.07131.x. PMID: 19583775

Nitric oxide produces HLA-G nitration and induces metalloprotease-dependent shedding creating a tolerogenic milieu. Díaz-Lagares A, Alegre E, LeMaoult J, Carosella ED, González A. Immunology. 2009 Mar;126(3):436-45. doi: 10.1111/j.1365-2567.2008.02911.x. PMID: 18764882

Preliminary results of the combination of bevacizumab and weekly Paclitaxel in advanced melanoma. González-Cao M, Viteri S, Díaz-Lagares A, González A, Redondo P, Nieto Y, Espinós J, Chopitea A, Ponz M, Martín-Algarra S. Oncology. 2008;74(1-2):12-6. doi: 10.1159/000138351. PMID: 18536525

Study of the plasmatic levels of tryptophan and kynurenine throughout pregnancy. Alegre E, López AS, Díaz-Lagares A, González A. Clin Chim Acta. 2008 Jul 17;393(2):132-3. doi: 10.1016/j.cca.2008.03.011. PMID: 18402779

Effect of 3-hydroxyanthranilic acid in the immunosuppressive molecules indoleamine dioxygenase and HLA-G in macrophages. López AS, Alegre E, Díaz-Lagares A, García-Girón C, Coma MJ, González A. Immunol Lett. 2008 Apr 15;117(1):91-5. doi: 10.1016/j.imlet.2008.01.001. PMID: 18289708

Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy. Alegre E, Díaz-Lagares A, Lemaoult J, López-Moratalla N, Carosella ED, González A. Hum Immunol. 2007 Aug;68(8):661-7. PMID: 17678720


fidis_logotipo_web-120
logo-centro
ONC