Pharmacoepigenetics
Our ultimate goal is to understand the pharmacological response and identify new biomarkers that are amenable for targeted manipulation. Our strategy is to combine genetic and epigenetic state-of-the-art analyses of clinical samples and functional studies in advanced three-dimensional cell cultures.
We developed a method that distinguishes DNA methylation from hydroxymethylation, and identified variants specific to each of these cytosine modifications important for drug metabolism (Nucleic Acids Research, 2016).
We have recently applied this principle to the identification of the first epigenetic marker of response to cancer immunotherapy (Lancer Resp. Med., 2018, Best Practice, 2019). In addition, we have identified a novel transcriptomic signature of B cell functionality associated with survival in melanoma patients treated with immunotherapy (IJMS 2023).
Another interesting aspect of our research is Abscopal Response, a distant response in a non-irradiated tumor after radiotherapy in other lesions. We have reported a 65% Abscopal Response rate that was associated with an improved Progression-Free Survival (21.2 months vs 3 months, p < 0.0001) in patients that were treated with the combination of Radiotherapy and Immunotherapy (International Journal of Radiation Oncology, 2022).
Our recent projects incorporate this combination therapy with the aim of characterizing the immunogenic cell death that Immune Checkpoint Blockade triggers in those patients developing Abscopal Response.
Specialised methods
- Three-dimensional cultures (and treatment/phenotyping) of primary human liver cells and cancer cell lines.
- High-throughput 3D cultures in 96-well plates using hanging drop technology (© InSphero) or Ultra Low Attachment surfaces.
- TET-assisted bisulfite conversion (TAB)-based determination of DNA methylation and hydroxymethylation:
- TAB-EPIC Illumina DNA methylation arrays for genome-wide analysis of 850K CpG sites
- TAB-Methyl-Seq Agilent targeted libraries for Next Generation Sequencing
- TAB-Sanger sequencing
- Adaptations of the protocol for FFPE and cell-free DNA
- TET-independent restriction-based determination of DNA methylation and hydroxymethylation
- Quantification of global DNA methylation and hydroxymethylation by mass spectrometry/liquid chromatography.
- Smart-seq library preparation for single cell RNA-sequencing.
- All RNA-sequencing by ribosomal depletion
- Exome sequencing with DNA from FFPE tumors and paired PBMCs
- ChIP-qPCR for histone modifications in 3D liver cancer cell lines and primary hepatocyte microtissues.
- Bioinformatics for genome-wide and customised transcriptomic/epigenomic analyses. OMICS integration. AI-based prediction models.
Group members
Isabel Barragan – Research group leader
Laura Espino – Postdoc
Andre Nobre – Postdoc
Shady Sayed – Master thesis student
Open positions
Candidates that are interested in predoctoral and postdoctoral positions please send your personal letter and CV to Isabel Barragan, research group leader. Support for external funding applications may also be provided.
Selected financial support
- STINT China-Sweden: Identification of DNA methylation and hydroxymethylation variation and molecular network in primary central nervous system lymphoma
- ProyExcel_01002: Precision pharmacogenomics of immunotherapy treatment of lung and head and neck cancer. Andalusian Government, Science.
- PI22/01816: Immunotherapy resistance biomarker: integrating Abscopal Response and epigenetics in a non-invasive precision medicine strategy. Health Institute Carlos III.
- SEOM21: MicroRNA signatures in the early detection of the field cancerization in squamous cell oral cavity carcinoma.
- AECC 2020: Radio-immunotherapy in metastatic cancer.
- P20-01326: ORIGEN: Early detection of liver metastases in breast cancer based on the study of methylation and hydroximetylation patterns in the circulating free DNA in blood. Andalusian Government, Science.
- PI18/01592: Omics integration for precision cancer immunotherapy. Health Institute Carlos III.
- Metabolic therapy against cancer: tumoral suppression induced by glutaminase dysregulation. Spanish Ministry of Science.
- GEM20: Determination of genetic and epigenetic variants associated with response to immune checkpoint inhibitors in cancer. Best Melanoma Research Project.
- COV20-62050: Identification of susceptibility factors for SARS-CoV-2 infection and severity of COVID19 in patients treated with Immune Checkpoint Blockade. Andalusian Government, Science.
- PI-0121-2020: Prospective longitudinal study of genetic, epigenetic and cell populations markers of response to Immune Checkpoint Blockade in melanoma. Andalusian Government, Health.
Publications (2019-2023)
Oliver J, Onieva JL, Garrido-Barros M, Cobo-Dols M, Martínez-Gálvez B, García-Pelícano AI, Dubbelman J, Benítez JC, Martín JZ, Cantero A, Perez-Ruiz E, Rueda-Dominguez A, Barragan I. Fluorometric Quantification of Total Cell-Free DNA as a Prognostic Biomarker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Blockade. Cancers 2023, 15, 3357. https:// doi.org/10.3390/cancers15133357
Chaves P, Garrido M, Oliver J, Pérez-Ruiz E, Barragan I, Rueda-Domínguez A. Preclinical models in head and neck squamous cell carcinoma. Br J Cancer. 2023 May;128(10):1819-1827. doi: 10.1038/s41416-023-02186-1. Epub 2023 Feb 10. Review. PubMed PMID: 36765175; PubMed Central PMCID: PMC10147614.
Chicas-Sett R, Zafra J, Rodriguez-Abreu D, Castilla-Martinez J, Benitez G, Salas B, Hernandez S, Lloret M, Onieva JL, Barragan I, Lara PC. Combination of SABR With Anti-PD-1 in Oligoprogressive Non-Small Cell Lung Cancer and Melanoma: Results of a Prospective Multicenter Observational Study. Int J Radiat Oncol Biol Phys. 2022 Nov 15;114(4):655-665. doi: 10.1016/j.ijrobp.2022.05.013. Epub 2022 May 18. PubMed PMID: 35595158.
Guardamagna M, Berciano-Guerrero MA, Villaescusa-González B, Perez-Ruiz E, Oliver J, Lavado-Valenzuela R, Rueda-Dominguez A, Barragán I, Queipo-Ortuño MI. Gut Microbiota and Therapy in Metastatic Melanoma: Focus on MAPK Pathway Inhibition. Int J Mol Sci. 2022 Oct 9;23(19). doi: 10.3390/ijms231911990. Review. PubMed PMID: 36233289; PubMed Central PMCID: PMC9569448.
Oliver J, Onieva JL, Garrido-Barros M, Berciano-Guerrero MÁ, Sánchez-Muñoz A, José Lozano M, Farngren A, Álvarez M, Martínez-Gálvez B, Pérez-Ruiz E, Alba E, Cobo M, Rueda-Domínguez A, Barragán I. Association of Circular RNA and Long Non-Coding RNA Dysregulation with the Clinical Response to Immune Checkpoint Blockade in Cutaneous Metastatic Melanoma. Biomedicines. 2022 Sep 27;10(10). doi: 10.3390/biomedicines10102419. PubMed PMID: 36289681; PubMed Central PMCID: PMC9599084.
Berciano-Guerrero MA, Guardamagna M, Perez-Ruiz E, Jurado JM, Barragán I, Rueda-Dominguez A. Treatment of Metastatic Melanoma at First Diagnosis: Review of the Literature. Life (Basel). 2022 Aug 24;12(9). doi: 10.3390/life12091302. Review. PubMed PMID: 36143339; PubMed Central PMCID: PMC9505710.
Onieva JL, Xiao Q, Berciano-Guerrero MÁ, Laborda-Illanes A, de Andrea C, Chaves P, Piñeiro P, Garrido-Aranda A, Gallego E, Sojo B, Gálvez L, Chica-Parrado R, Prieto D, Pérez-Ruiz E, Farngren A, Lozano MJ, Álvarez M, Jiménez P, Sánchez-Muñoz A, Oliver J, Cobo M, Alba E, Barragán I. High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade. Int J Mol Sci. 2022 Aug 15;23(16). doi: 10.3390/ijms23169124. PubMed PMID: 36012390; PubMed Central PMCID: PMC9408876.
Oliver J, Garcia-Aranda M, Chaves P, Alba E, Cobo-Dols M, Onieva JL, Barragan I. Emerging non-invasive methylation biomarkers of cancer prognosis and drug response prediction. Semin Cancer Biol. 2022 Aug;83:584-595. doi: 10.1016/j.semcancer.2021.03.012. Epub 2021 Mar 20. Review. PubMed PMID: 33757849.
Søndergaard JN, Sommerauer C, Atanasoai I, Hinte LC, Geng K, Guiducci G, Bräutigam L, Aouadi M, Stojic L, Barragan I, Kutter C. CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism. Gut. 2022 Jan 12;. doi: 10.1136/gutjnl-2021-325109. [Epub ahead of print] PubMed PMID: 35022268; PubMed Central PMCID: PMC9484377.
Pérez-Ruiz E, Gutiérrez V, Muñoz M, Oliver J, Sánchez M, Gálvez-Carvajal L, Rueda-Domínguez A, Barragán I. Liquid Biopsy as a Tool for the Characterisation and Early Detection of the Field Cancerization Effect in Patients with Oral Cavity Carcinoma. Biomedicines. 2021 Oct 15;9(10). doi: 10.3390/biomedicines9101478. Review. PubMed PMID: 34680596; PubMed Central PMCID: PMC8533108.
Barragan I. Epigenetics modulates the complexity of the response to Immune Checkpoint Blockade. EBioMedicine. 2020 Oct;60:103005. doi: 10.1016/j.ebiom.2020.103005. Epub 2020 Sep 26. PubMed PMID: 32987318; PubMed Central PMCID: PMC7522086.
Gasca J, Flores ML, Jiménez-Guerrero R, Sáez ME, Barragán I, Ruíz-Borrego M, Tortolero M, Romero F, Sáez C, Japón MA. EDIL3 promotes epithelial-mesenchymal transition and paclitaxel resistance through its interaction with integrin αVβ3 in cancer cells. Cell Death Discov. 2020;6:86. doi: 10.1038/s41420-020-00322-x. eCollection 2020. PubMed PMID: 33014430; PubMed Central PMCID: PMC7494865.
Chica-Parrado MR, Godoy-Ortiz A, Jiménez B, Ribelles N, Barragan I, Alba E. Resistance to Neoadjuvant Treatment in Breast Cancer: Clinicopathological and Molecular Predictors. Cancers (Basel). 2020 Jul 22;12(8). doi: 10.3390/cancers12082012. Review. PubMed PMID: 32708049; PubMed Central PMCID: PMC7463925.
Xiao Q, Nobre A, Piñeiro P, Berciano-Guerrero MÁ, Alba E, Cobo M, Lauschke VM, Barragán I. Genetic and Epigenetic Biomarkers of Immune Checkpoint Blockade Response. J Clin Med. 2020 Jan 20;9(1). doi: 10.3390/jcm9010286. Review. PubMed PMID: 31968651; PubMed Central PMCID: PMC7019273.
Lauschke VM, Nordling Å, Zhou Y, Fontalva S, Barragan I, Ingelman-Sundberg M. CYP3A5 is unlikely to mediate anticancer drug resistance in hepatocellular carcinoma. Pharmacogenomics. 2019 Oct;20(15):1085-1092. doi: 10.2217/pgs-2019-0094. PubMed PMID: 31588878.
Recent conference communications
Oral presentation and abstract: Crossomics interactions for the identification of new biomarkers in hepatocellular carcinoma. Kasela S, Ivanov M, SayedS, Nobre A, Espino L, Marabita F, Milani L, Barragán I. Selected talk for the Emerging Researchers Forum. XXXIX Congress of SEBBM (Spanish Society of Biochemistry and Molecular Biology). Salamanca, Spain September 5-8th 2016.
Abstract: The development of TAB-Methyl-SEQ protocol for targeted profiling of 5-(hydroxy)methylcytosine with single base resolution by next-generation sequencing. Ivanov M, Kals M, Lauschke V, Barragan I, Milani L, Ingelman-Sundberg M. Gordon Research Conference on Epigenetics, Waltham, MA, USA, August 2-7, 2015.
Abstract: TAB-Methyl-SEQ protocol for targeted Next-generation sequencing of DNA (hydroxy)methylation: implications for ADME gene regulation. Ivanov M, Kals M, Lauschke V, Barragan I, Milani L, Ingelman-Sundberg M. ISSX Meeting 2015, Glasgow, UK, June 22-25, 2015.
Conference paper: Abundance and distribution of hydroxymethylcytosine (5hmC) in human liver. Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K, Rane A, Metspalu A, Milani L, Ingelman-Sundberg M. 20th International Symposium on Microsomes and Drug Oxidations, Stuttgart, Germany, May 18-25, 2014.
Abstract (Finalist of poster awards): Evaluation of a stem-cell derived in vitro system as a model for statin induced myotoxicity. Barragan I, Peric D, Laustriat D, Giraud-Triboult K, Peschanski M, Ingelman-Sundberg M. 20th International Symposium on Microsomes and Drug Oxidations. Stuttgart, Germany, May 18–22, 2014.
Abstract: The quantification and genome-wide mapping of 5- hydroxymethylcytosine in fetal and adult human livers. Ivanov M, Kals M, Kacevska M, Barragan I, Kasuga K, Rane A, Metspalu A, Milani L, Ingelman-Sundberg M. Gordon Research Conference on Epigenetics, Smithfield, MA, USA, August 4-9, 2013.
Abstract: No association between CYP2W1 variant alleles G541A (Ala181Thr) or C1463T (Pro448Leu) and colorectal cancer risk. Stenstedt K, Barragan I, Johansson I, Lindblom A, Ingelman Sundberg M, Edler D. ESCP's 7th Scientific & Annual Meeting, Vienna, September 26-28 2012.
Abstract: The hollow fiber 3D bioreactor: a tool for studies of hepatotoxicity. F Noor, D Mueller, K Zeilinger, I Barragan, I Johansson, P Gunness, L Sivertsson, E Heinzle, M Ingelman-Sundberg. SEURAT (Towards the replacement of in vivo repeated dose systemic toxicity testing)-1 - 2nd Annual meeting, Lisbon, Portugal, February 8-9 2012
Published abstract: Mutation screening of multiple genes in Spanish patients with Autosomal Recessive Retinitis Pigmentosa using a Custom designed Resequencing microarray. González-Del Pozo M, Pieras J, Barragán I, Naranjo B, Matamala N, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.
Published abstract: Novel study of copy number variations in EYS using the multiple ligation-dependent probe amplification (MLPA) technique. Pieras J, Barragán I, González-Del Pozo M, Matamala N, Audo I, Bernal S, Baiget M, Zeitz C, Bhattacharya S, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.
Published abstract: Haplotype analysis of EYS mutations identified in different European populations. Barragán I, Matamala N, González-Del Pozo M, Pieras J, Littink K, Cremers F, Borrego S, Antiñolo G. European Human Genetics Conference 2011. European Journal of Human Genetics 19, 380 ISSN/ISBN: 1018-4813 Amsterdam, the Netherlands, May 38-31 2011.
Published commentaries
News and views on the published article
EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa. Photoreceptors in evolution and disease.
Cook B, Zelhof AC. Nat Genet. 2008 Nov;40(11):1275-6. doi: 10.1038/ng1108-1275.
Collaborations
International collaborators
- Dr Carmen Saez (Pathologist and group leader of Endocrine Tumorigenesis and Hormonal Regulation of Cancer at the Institute of Biomedicine of Seville, Spain): anticancer therapy resistance phenotyping and proteomics.
- Dr Hua You (Oncologist and Assistant Professor at the Department of Oncology of the Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China): circulating DNA biomarkers of cancer.
- Dr Lili Milani (Senior Researcher and Head of Genotyping and Sequencing Core Facility, Estonian Genome Center): bioinformatics for NGS-based epigenomic analyses.
National collaborators
- Dr Jorge Ruas (Associate Professor and group leader of the group Molecular and Cellular Exercise Physiology at the Department of Physiology and Pharmacology, Karolinska Institutet): isoform-specific transcriptional reprogramming