Manel Esteller

Manel Esteller estudia les alteracions genètiques de les malalties. Ha participat en el desenvolupament de fàrmacs per tractar el càncer i de noves tecnologies per a la investigació en aquest àmbit.Manel Esteller estudia las alteraciones genéticas de las enfermedades. Ha participado en el desarrollo de fármacos para tratar el cáncer y de nuevas tecnologías para la investigación en este ámbito

Biological and Molecular Factors Predicting Response to Adoptive Cell Therapies in Cancer

GF is recipient of Marie Skłodowska-Curie Action individual fellowship (H2020-MSCA-IF-2019 - 896403). We thank CERCA Programme/Generalitat de Catalunya for institutional support. Work at ME laboratory is supported by the Health Department PERIS-project no. SLT/002/16/00374 and AGAUR-project no. 2017SGR1080 of the Catalan Government (Generalitat de Catalunya); Ministerio de Ciencia e Innovación (MCI), Agencia Estatal de Investigación (AEI) and European Regional Development Fund (ERDF) project no. RTI2018-094049-B-I00; the Cellex Foundation; and "la Caixa" Banking Foundation (LCF/PR/GN18/51140001).Adoptive cell therapy (ACT) constitutes a major breakthrough in cancer management that has expanded in the past years due to impressive results showing durable and even curative responses for some patients with hematological malignancies. ACT leverages antigen specificity and cytotoxic mechanisms of the immune system, particularly relying on the patient's T lymphocytes to target and eliminate malignant cells. This personalized therapeutic approach exemplifies the success of the joint effort of basic, translational, and clinical researchers that has turned the patient's immune system into a great ally in the search for a cancer cure. ACTs are constantly improving to reach a maximum beneficial clinical response. Despite being very promising therapeutic options for certain types of cancers, mainly melanoma and hematological malignancies, these individualized treatments still present several shortcomings, including elevated costs, technical challenges, management of adverse side effects, and a limited population of responder patients. Thus, it is crucial to discover and develop reliable and robust biomarkers to specifically and sensitively pinpoint the patients that will benefit the most from ACT as well as those at higher risk of developing potentially serious toxicities. Although unique readouts of infused cell therapy success have not yet been identified, certain characteristics from the adoptive cells, the tumor, and/or the tumor microenvironment have been recognized to predict patients' outcome on ACT. Here, we comment on the importance of biomarkers to predict ACT chances of success to maximize efficacy of treatments and increase patients' survival

Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer

Jass J R, Baker K, Zlobec I, Higuchi T, Barker M, Buchanan D & Young J (2006) Histopathology 49, 121–131 Advanced colorectal polyps with the molecular and morphological features of serrated polyps and adenomas: concept of a ‘fusion’ pathway to colorectal cancer AIM: To establish and explain the pattern of molecular signatures across colorectal polyps. METHODS AND RESULTS: Thirty-two sessile serrated adenomas (SSA), 10 mixed polyps (MP), 15 traditional serrated adenomas (SA), 49 hyperplastic polyps (HP) and 84 adenomas were assessed for mutation of KRAS and BRAF and aberrant expression of p53. The findings were correlated with loss of expression of O-6-methylguanine DNA methyltransferase (MGMT). KRAS mutation occurred more frequently (26.5%) than BRAF mutation (4.8%) in adenomas (P < 0.001) and particularly in adenomas with villous architecture (50%). Loss of expression of MGMT correlated with KRAS mutation in small tubular adenomas (P < 0.04). BRAF mutation was frequent in HPs (67%) and SSAs (81%), while KRAS mutation was infrequent (4% and 3%, respectively). Of MPs and SAs, 72% had either BRAF or KRAS mutation. Aberrant expression of p53 was uncommon overall, but occurred more frequently in MPs and SAs (12%) than adenomas (1%) (P < 0.04) and there was concordant loss of expression of MGMT. CONCLUSIONS: Molecular alterations that are characteristic of the serrated pathway and adenoma–carcinoma sequence can co-occur in a minority of advanced colorectal polyps that then show morphological features of both pathways. These lesions account for only 2% of colorectal polyps, but may be relatively aggressive

Towards a more precise therapy in cancer : Exploring epigenetic complexity

The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. Research at F.P.C lab is supported by by Gobierno Vasco/Eusko Jaurlaritza (IT-324-07) and by 2020 Framework Programme of the European Union (Euro-Cholangio-Net CA18122).A plethora of preclinical evidences suggests that pharmacological targeting of epigenetic dysregulation is a potent strategy to combat human diseases. Nevertheless, the implementation of epidrugs in clinical practice is very scarce and mainly limited to haematological malignancies. In this review, we discuss cutting-edge strategies to foster the chemical design, the biological rationale and the clinical trial development of epidrugs. Specifically, we focus on the development of dual hybrids to exploit multitargeting of key epigenetic molecules deregulated in cancer; the study of epigenetic-synthetic lethality interactions as a mechanism to address loss-of-function mutations, and the combination of epidrugs with other therapies such as immunotherapy to avoid acquired chemoresistance and increase therapy sensitivity. By exploring these challenges, among others, the field of epigenetic chemical biology will increase its potential for clinical benefit, and more effective strategies targeting the aberrant epigenome in cancer are likely to be developed both in haematological and solid tumours

The chromatin remodeling factor CHD8 interacts with elongating RNA polymerase II and controls expression of the cyclin E2 gene

CHD8 is a chromatin remodeling ATPase of the SNF2 family. We found that depletion of CHD8 impairs cell proliferation. In order to identify CHD8 target genes, we performed a transcriptomic analysis of CHD8-depleted cells, finding out that CHD8 controls the expression of cyclin E2 (CCNE2) and thymidylate synthetase (TYMS), two genes expressed in the G1/S transition of the cell cycle. CHD8 was also able to co-activate the CCNE2 promoter in transient transfection experiments. Chromatin immunoprecipitation experiments demonstrated that CHD8 binds directly to the 5′ region of both CCNE2 and TYMS genes. Interestingly, both RNA polymerase II (RNAPII) and CHD8 bind constitutively to the 5′ promoter-proximal region of CCNE2, regardless of the cell-cycle phase and, therefore, of the expression of CCNE2. The tandem chromodomains of CHD8 bind in vitro specifically to histone H3 di-methylated at lysine 4. However, CHD8 depletion does not affect the methylation levels of this residue. We also show that CHD8 associates with the elongating form of RNAPII, which is phosphorylated in its carboxy-terminal domain (CTD). Furthermore, CHD8-depleted cells are hypersensitive to drugs that inhibit RNAPII phosphorylation at serine 2, suggesting that CHD8 is required for an early step of the RNAPII transcription cycle

The DNA methylation landscape of hematological malignancies : an update

Altres ajuts: the Cellex Foundation; and la Caixa Banking Foundation (LCF/PR/GN18/51140001).The rapid advances in high-throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy

Disruption of the RNA modifications that target the ribosome translation machinery in human cancer

Genetic and epigenetic changes deregulate RNA and protein expression in cancer cells. In this regard, tumors exhibit an abnormal proteome in comparison to the corresponding normal tissues. Translation control is a crucial step in the regulation of gene expression regulation under normal and pathological conditions that ultimately determines cellular fate. In this context, evidence shows that transfer and ribosomal RNA (tRNA and rRNA) modifications affect the efficacy and fidelity of translation. The number of RNA modifications increases with the complexity of organisms, suggesting an evolutionary diversification of the possibilities for fine-tuning the functions of coding and non-coding RNAs. In this review, we focus on alterations of modifications of transfer and ribosomal RNA that affect translation in human cancer. This variation in the RNA modification status can be the result of altered modifier expression (writers, readers or erasers), but also due to components of the machineries (C/D or H/ACA boxes) or alterations of proteins involved in modifier expression. Broadening our understanding of the mechanisms by which site-specific modifications modulate ribosome activity in the context of tumorigenesis will enable us to enrich our knowledge about how ribosomes can influence cell fate and form the basis of new therapeutic opportunities

The Contribution of Epigenetics to Cancer Immunotherapy

Altres ajuts: This work was supported by the the Cellex Foundation; and La Caixa Banking Foundation (LCF/PR/GN18/51140001).Effective anticancer immunotherapy treatments constitute a qualitative leap in cancer management. Nonetheless, not all patients benefit from such therapies because they fail to achieve complete responses, suffer frequent relapses, or develop potentially life-threatening toxicities. Epigenomic signatures in immune and cancer cells appear to be accurate and promising predictors of patient outcomes with immunotherapy. In addition, combined treatments with epigenetic drugs can exploit the dynamic nature of epigenetic changes to potentially modulate responses to immunotherapy. Candidate epigenetic biomarkers may provide a rationale for patient stratification and precision medicine, thus maximizing the chances of treatment success while minimizing unwanted effects. We present a comprehensive up-to-date view of potential epigenetic biomarkers in immunotherapy and discuss their advantages over other indicators

Epigenetics as a mechanism driving polygenic clinical drug resistance

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs. Although laboratory-based models of acquired resistance to anticancer agents tend to focus on specific genes or biochemical pathways, such 'one gene : one outcome' models may be an oversimplification of acquired resistance to treatment of cancer patients. Instead, clinical drug resistance may be due to changes in expression of a large number of genes that have a cumulative impact on chemosensitivity. Aberrant CpG island methylation of multiple genes occurring in a nonrandom manner during tumour development and during the acquisition of drug resistance provides a mechanism whereby expression of multiple genes could be affected simultaneously resulting in polygenic clinical drug resistance. If simultaneous epigenetic regulation of multiple genes is indeed a major driving force behind acquired resistance of patients' tumour to anticancer agents, this has important implications for biomarker studies of clinical outcome following chemotherapy and for clinical approaches designed to circumvent or modulate drug resistance