Josep Carreras Leukaemia Research Institute
Can Ruti CampusCtra de Can Ruti, Camí de les Escoles s/n08916 Badalona, Barcelona
The group continues the wide-ranging work on epigenetics that Manel Esteller, the group leader, has carried out during his career until now. Current research is devoted to the establishment of the epigenome and epitranscriptome maps for normal and transformed cells, the study of the interactions between epigenetic modifications and non-coding RNAs, and the development of new epigenetic drugs for cancer therapy.
Our laboratory is one of those responsible for establishing the observation that epigenetic disruption of mRNA transcription, particularly in DNA methylation and histone modification patterns, contribute to the initiation and progression of human tumours (reviewed in Esteller, N Engl J Med 2008; Heyn and Esteller, Nat Rev Genet 2012).
It has also been recognized that microRNAs (small non-coding RNAs that regulate gene expression by sequence-specific base pairing in mRNA targets) also play a key role in the biology of the cell, and can have an impact on the development of cancer. In this context, we characterized the first miRNA undergoing specific cancer-methylation associated silencing (Lujambio et al., Cancer Res 2007), followed by the characterization of many other miRNAs disrupted in the same manner (Lujambio et al., PNAS 2008; Davalos et al., Oncogene 2012).
We have also studied other types of ncRNA, such as subclasses of lncRNA, undergoing aberrant DNA methylation events in human cancer (Lujambio et al., Oncogene 2010; Guil et al, Nat Struc Mol Biol 2012; Liz et al., Mol Cell 2014; Diaz-Lagares et al., PNAS 2016). We have shown that sometimes these epigenetic lesions occur outside the minimal promoters and take place in enhancers (Heyn et al., Genome Biol 2016; Vidal et al, Oncogene 2017) or at cryptic internal promoters (Vizoso et al., Nature Medicine 2015).
Our group has also had a long-standing interest in translating the use of epigenetic knowledge gained from research into biomarkers to predict clinical outcome and to assay new drugs to reverse the distorted epigenetic landscape (Berdasco and Esteller, Nature Review Genetics 2019). For example, we have used epigenetic markers to predict response to anti-tumour therapies and following the initial observation that MGMT gene methylation predicted response to alkylating agents in glioma (Esteller et al., N Engl J Med 2000), we have found many such relationships. We have shown the relationship of methylation of MGMT with the response to alkylating agents in lymphoma (Esteller et al., J Natl Cancer Inst, 2002); of WRN with the response to irinotecan (Agrelo et al., Proc Natl Acad Sci USA, 2006); of BRCA1 with the response to PARP inhibitors (Veeck et al., J Natl Cancer Institute, 2010) and of DERL3 with the response to glycolysis inhibitors (Lopez-Serra et al., Nature Communications, 2014). Methylation of SRBC (Moutinho et al. J Natl Cancer Institute, 2014) and SLFN11 (Nogales et al., Oncotarget 2015) have also been identified as resistance markers for platinum derivatives in human tumours and the regulator of EGFR TBC1D16 has been identified as a sensitizer for therapies with BRAF and MEK inhibitors (Vizoso et al., Nature Medicine 2015). Recent discoveries indicate that SVIP is related to the response to GLUT1 inhibitors (Llinas-Arias et al. JCI Insight 2019).
Continuing with this translational side of our work, we are also interested in the development and study of new epigenetic drugs that target DNA methylation and histone modification writers, readers and erasers and could have an anti-cancer effect (Lara et al Oncogene 2008; Zubia et al Oncogene 2009; Huertas et al., Oncogene 2012; Perez-Salvia et al., Oncotarget 2017; Perez-Salvia et al., Haematologica 2018).
Interestingly, the “repertoire” of epigenetic modifications of DNA is fairly limited, as we recently reviewed (Heyn and Esteller, Cell 2015). In sharp contrast, more than one hundred post-transcriptional modifications occur in RNA (Esteller and Pandolfi, Cancer Discovery 2017; Davalos et al., Cell 2018). Until very recently it was almost impossible to make a good map of the epigenetic modifications of the RNA molecule, which hampered many studies in this area and prevented advances in the study of the significance of each RNA modification. However, recent methodologies now allow the study of the so-called epitranscriptome. In this field, we have shown aberrant RNA editing mediated by ADAR1 amplification (Anadon et al., Oncogene 2016) and altered RNA decapping mediated by NUDT16 epigenetic silencing (Anadon et al., Leukemia 2017). Knowledge in this area is limited and its study is the focus of intense research in the lab.
We have also a long-standing vocation for research in monogenic disorders affecting epigenetic genes (Urdinguio et al., Lancet Neurol. 2009), particularly in Rett syndrome. The disease is associated with a germline mutation in MECP2, a protein that it is attracted to methylated DNA. Over the years, we have identified the gene targets for MECP2 (Ballestar et al., EMBO J 2013; Petazzi et al. RNA Biol. 2013, Neurobiol Dis. 2014), studied the genomics of Rett syndrome in detail (Saez et al., Genet Med 2016; Lucariello et al., Hum Genet 2016) and developed pre-clinical drug studies (Szczesna et al., Neuropsychopharmacology et al., 2014; Jorge-Torres et al., Cell Reports 2018). In a similar context, we are also curious about the epigenomic profiles of common diseases such as cardiovascular alterations (Zaina et al., Circ Cardiovasc Genet. 2014; Valencia-Morales et al., BMC Med Genomics 2015) and Alzheimer and other neurodegenerative diseases (Sanchez-Mut et al., Brain et al., 2013; Hipoccampus 2014; Transl Psychiatry. 2016; Nature Medicine, 2018).
Finally, we have a strong interest in the establishment of new epigenomic platforms to elaborate comprehensive DNA methylome maps, our lab is the pioneer in the validation of the commonly used DNA methylation microarrays such as the 450K (Sandoval et al., Epigenetics 2011) and the EPIC/850K (Moran et al. Epigenomics 2016). The use of these approaches has made several breakthroughs possible, such as: the establishment of DNA methylation signatures that are predictive of early dissemination in lung cancer (Sandoval et al., JCO 2010); the diagnosis of the tumor type in Cancer of Unknown Primary (CUP) (Moran et al., Lancet Oncology 2016); or better understanding of the response to anti-PD1 immunotherapy (Duruisseaux et al., The Lancet Respiratory Medicine 2018).
2019 Lansdowne Lecture Award, University of Victoria, British Columbia, Canada
2018 Scientific Achievements Prize, Foundation for the Excellence in Oncology (ECO)
2018 Scientific Innovation Award Team in Clinical Research, Pfizer Foundation
2018 Award for the Best Science and Humanities Dissemination Activities by the Board of Trustees and the Doctors' Senate of the University of Barcelona (UB)
2018 Innovation Health Award in Oncology by Celgene Endowment
2017 “Carlemagne Falcon” Award, Girona, Catalonia
2017 Best Ideas in Health, Epitranscriptome, Diario Medico
2016 Honour Gold Medal, Government of Catalonia (Generalitat de Catalunya)
2016 Premi Internacional de Catalunya, Generalitat de Catalunya
2016 Best Ideas in Health, EPICUP, Diario Medico
2016 European Research Council Proof of Concept Grant
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