RESUMEN
One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3+CD8+ T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3+CD8+ T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient's mutanome and immune microenvironment.
Asunto(s)
Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Antígenos de Neoplasias/metabolismo , Inmunoterapia , Inflamación , Microambiente TumoralRESUMEN
The treatment of colorectal cancer (CRC) is an unmet medical need in absence of early diagnosis. Here, upon characterizing cancer-specific transposable element-driven transpochimeric gene transcripts (TcGTs) produced by this tumor in the SYSCOL cohort, we find that expression of the hominid-restricted retrogene POU5F1B through aberrant activation of a primate-specific endogenous retroviral promoter is a strong negative prognostic biomarker. Correlating this observation, we demonstrate that POU5F1B fosters the proliferation and metastatic potential of CRC cells. We further determine that POU5F1B, in spite of its phylogenetic relationship with the POU5F1/OCT4 transcription factor, is a membrane-enriched protein that associates with protein kinases and known targets or interactors as well as with cytoskeleton-related molecules, and induces intracellular signaling events and the release of trans-acting factors involved in cell growth and cell adhesion. As POU5F1B is an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, our data provide interesting leads for the development of cancer therapies.
Asunto(s)
Neoplasias Colorrectales , Genes Homeobox , Proteínas de Homeodominio , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis de la Neoplasia , FilogeniaRESUMEN
Efforts to precisely identify tumor human leukocyte antigen (HLA) bound peptides capable of mediating T cell-based tumor rejection still face important challenges. Recent studies suggest that non-canonical tumor-specific HLA peptides derived from annotated non-coding regions could elicit anti-tumor immune responses. However, sensitive and accurate mass spectrometry (MS)-based proteogenomics approaches are required to robustly identify these non-canonical peptides. We present an MS-based analytical approach that characterizes the non-canonical tumor HLA peptide repertoire, by incorporating whole exome sequencing, bulk and single-cell transcriptomics, ribosome profiling, and two MS/MS search tools in combination. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides, including an immunogenic peptide derived from an open reading frame downstream of the melanoma stem cell marker gene ABCB5. These findings hold great promise for the discovery of previously unknown tumor antigens for cancer immunotherapy.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Melanoma/genética , Melanoma/inmunología , Péptidos/genética , Proteogenómica , Secuencia de Aminoácidos , Línea Celular Tumoral , Bases de Datos de Proteínas , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Péptidos/química , ARN/genética , ARN/metabolismo , Linfocitos T/metabolismoRESUMEN
BET bromodomain inhibitors, which have an antitumoral effect against various solid cancer tumor types, have not been studied in detail in luminal breast cancer, despite the prevalence of this subtype of mammary malignancy. Here we demonstrate that the BET bromodomain inhibitor JQ1 exerts growth-inhibitory activity in human luminal breast cancer cell lines associated with a depletion of the C-MYC oncogene, but does not alter the expression levels of the BRD4 bromodomain protein. Interestingly, expression microarray analyses indicate that, upon JQ1 administration, the antitumoral phenotype also involves downregulation of relevant breast cancer oncogenes such as the Breast Carcinoma-Amplified Sequence 1 (BCAS1) and the PDZ Domain-Containing 1 (PDZK1). We have also applied these in vitro findings in an in vivo model by studying a transgenic mouse model representing the luminal B subtype of breast cancer, the MMTV-PyMT, in which the mouse mammary tumor virus promoter is used to drive the expression of the polyoma virus middle T-antigen to the mammary gland. We have observed that the use of the BET bromodomain inhibitor for the treatment of established breast neoplasms developed in the MMTV-PyMT model shows antitumor potential. Most importantly, if JQ1 is given before the expected time of tumor detection in the MMTV-PyMT mice, it retards the onset of the disease and increases the survival of these animals. Thus, our findings indicate that the use of bromodomain inhibitors is of great potential in the treatment of luminal breast cancer and merits further investigation.
RESUMEN
Recent efforts to sequence human cancer genomes have highlighted that point mutations in genes involved in the epigenetic setting occur in tumor cells. Small cell lung cancer (SCLC) is an aggressive tumor with poor prognosis, where little is known about the genetic events related to its development. Herein, we have identified the presence of homozygous deletions of the candidate histone acetyltransferase KAT6B, and the loss of the corresponding transcript, in SCLC cell lines and primary tumors. Furthermore, we show, in vitro and in vivo, that the depletion of KAT6B expression enhances cancer growth, while its restoration induces tumor suppressor-like features. Most importantly, we demonstrate that KAT6B exerts its tumor-inhibitory role through a newly defined type of histone H3 Lys23 acetyltransferase activity.
Asunto(s)
Carcinoma de Células Pequeñas/enzimología , Histona Acetiltransferasas/fisiología , Neoplasias Pulmonares/enzimología , Proteínas de Neoplasias/fisiología , Acetilación , Animales , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/farmacología , Camptotecina/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Resistencia a Antineoplásicos , Eliminación de Gen , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Xenoinjertos , Histona Acetiltransferasas/deficiencia , Histona Acetiltransferasas/genética , Histonas/metabolismo , Humanos , Irinotecán , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Desnudos , Metástasis de la Neoplasia , Proteínas de Neoplasias/deficiencia , Proteínas de Neoplasias/genética , Procesamiento Proteico-Postraduccional , Interferencia de ARN , ARN Mensajero/genética , ARN Neoplásico/genética , ARN Interferente Pequeño/farmacologíaRESUMEN
The Barcelona Conference on Epigenetics and Cancer (BCEC) was held in Barcelona, Spain, on October 1(st) and 2(nd), 2014. The meeting was co-organized by the Cancer Epigenetics and Biology Program (PEBC-IDIBELL) and B·Debate, an initiative of Biocat, with the support of "la Caixa" Foundation. The scientific committee was comprised of leading scientists in the field of epigenetics: Dr. Manel Esteller, director of PEBC-IDIBELL, Dr. Alejandro Vaquero and Dr. Esteban Ballestar, from PEBC-IDIBELL, Juan Ausió from the University of Victoria (Canada), and Marcus Buschbeck, from the Institute of Predictive and Personalized Medicine of Cancer (IMPPC), as BCEC series coordinator. This meeting was the second edition of the BCEC series, which was launched by 5 leading Barcelonan institutes to bring together leading investigators in the fields of epigenetics and chromatin research. The topics discussed during the meeting included the current challenges, opportunities, and perspectives surrounding the study of histone modifications (focusing in acetylation), chromatin structure and gene expression, and the involvement of histone acetylation in physiology and diseases, such as cancer or neurological diseases.
Asunto(s)
Epigénesis Genética , Histonas/metabolismo , Neoplasias/genética , Acetilación , Animales , Cromatina/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Enfermedades del Sistema Nervioso/genética , EspañaRESUMEN
Gene expression is dynamically controlled by epigenetics through post-translational modifications of histones, chromatin-associated proteins and DNA itself. All these elements are required for the maintenance of chromatin structure and cell identity in the context of a normal cellular phenotype. Disruption of epigenetic regulation is a common event in human cancer. Here, we review the key protein families that control epigenetic signalling through writing, erasing or reading specific post-translational modifications. By exploiting the leading role of epigenetics in tumour development and the reversibility of epigenetic modifications, promising novel epigenetic-based therapies are being developed. In this article, we highlight the emerging low MW inhibitors targeting each class of chromatin-associated protein, their current use in preclinical and clinical trials and the likelihood of their being approved in the near future.
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Antineoplásicos/farmacología , Epigénesis Genética/efectos de los fármacos , Histona Acetiltransferasas/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Histona Demetilasas/antagonistas & inhibidores , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Histonas/efectos de los fármacos , Neoplasias/genética , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Antineoplásicos/uso terapéutico , Inhibidores de Histona Desacetilasas/uso terapéutico , Histonas/metabolismo , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
Latest advances in genome technologies have greatly advanced the discovery of epigenetic genes altered in cancer. The initial single candidate gene approaches have been coupled with newly developed epigenomic platforms to hasten the convergence of scientific discoveries and translational applications. Here, we present an overview of the evolution of cancer epigenomics and an updated catalog of disruptions in epigenetic pathways, whose misregulation can culminate in cancer. The creation of these basic mutational catalogs in cell lines and primary tumors will provide us with enough knowledge to move diagnostics and therapy from the laboratory bench to the bedside.
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Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Mutación , Proteínas de Neoplasias/genética , Neoplasias/genética , Línea Celular Tumoral , Cromatina/química , Predisposición Genética a la Enfermedad , Genoma Humano , Genómica/tendencias , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patología , ARN no Traducido/genética , ARN no Traducido/metabolismo , Transducción de Señal , Investigación Biomédica TraslacionalRESUMEN
The immunodeficiency, centromere instability and facial anomalies (ICF) syndrome is associated to mutations of the DNA methyl-transferase DNMT3B, resulting in a reduction of enzyme activity. Aberrant expression of immune system genes and hypomethylation of pericentromeric regions accompanied by chromosomal instability were determined as alterations driving the disease phenotype. However, so far only technologies capable to analyze single loci were applied to determine epigenetic alterations in ICF patients. In the current study, we performed whole-genome bisulphite sequencing to assess alteration in DNA methylation at base pair resolution. Genome-wide we detected a decrease of methylation level of 42%, with the most profound changes occurring in inactive heterochromatic regions, satellite repeats and transposons. Interestingly, transcriptional active loci and ribosomal RNA repeats escaped global hypomethylation. Despite a genome-wide loss of DNA methylation the epigenetic landscape and crucial regulatory structures were conserved. Remarkably, we revealed a mislocated activity of mutant DNMT3B to H3K4me1 loci resulting in hypermethylation of active promoters. Functionally, we could associate alterations in promoter methylation with the ICF syndrome immunodeficient phenotype by detecting changes in genes related to the B-cell receptor mediated maturation pathway.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Síndromes de Inmunodeficiencia/genética , Linfocitos B , Línea Celular Transformada , Preescolar , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Epigénesis Genética , Cara/anomalías , Femenino , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Síndromes de Inmunodeficiencia/metabolismo , Mutación , Enfermedades de Inmunodeficiencia Primaria , Análisis de Secuencia de ADN , Sulfitos , ADN Metiltransferasa 3BRESUMEN
Disruption of the DNA methylation landscape is one of the most common features of human tumors. However, genetic alterations of DNA methyltransferases (DNMTs) have not been described in carcinogenesis. Herein, we show that pancreatic and breast cancer cells undergo gene amplification of the DNA methyltransferase 3B (DNMT3B). The presence of extra copies of the DNMT3B gene is linked to higher levels of the corresponding mRNA and protein. Most importantly, the elevated gene dosage of DNMT3B is associated with increased resistance to the growth-inhibitory effect mediated by DNA demethylating agents. In particular, cancer cells harboring DNMT3B gene amplification are less sensitive to the decrease in cell viability caused by 5-azacytidine (Vidaza), 5-aza-2-deoxycytidine (Decitabine), and SGI-1027. Overall, the data confirm DNMT3B as a bona fide oncogene in human cancer and support the incorporation of the DNMT3B copy number assay into current clinical trials assessing the efficacy of DNA demethylating drugs in solid tumors.
Asunto(s)
Antineoplásicos/farmacología , ADN (Citosina-5-)-Metiltransferasas/genética , Amplificación de Genes , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN/efectos de los fármacos , Decitabina , Resistencia a Antineoplásicos , Humanos , Hibridación Fluorescente in Situ , ARN Mensajero/metabolismo , ADN Metiltransferasa 3BRESUMEN
MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression at the posttranscriptional level and are critical for many cellular pathways. The disruption of miRNAs and their processing machineries also contributes to the development of human tumors. A common scenario for miRNA expression in carcinogenesis is emerging that shows that impaired miRNA production and/or down-regulation of these transcripts occurs in many neoplasms. Several of these lost miRNAs have tumor-suppressor features, so strategies to restore their expression globally in malignancies would be a welcome addition to the current therapeutic arsenal against cancer. Herein, we show that the small molecule enoxacin, a fluoroquinolone used as an antibacterial compound, enhances the production of miRNAs with tumor suppressor functions by binding to the miRNA biosynthesis protein TAR RNA-binding protein 2 (TRBP). The use of enoxacin in human cell cultures and xenografted, orthotopic, and metastatic mouse models reveals a TRBP-dependent and cancer-specific growth-inhibitory effect of the drug. These results highlight the key role of disrupted miRNA expression patterns in tumorigenesis, and suggest a unique strategy for restoring the distorted microRNAome of cancer cells to a more physiological setting.