RESUMEN
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animales , Ratones , Línea Celular Tumoral , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Páncreas/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Fibroblastos/metabolismo , Carcinogénesis/patología , Microambiente TumoralRESUMEN
Oncogenic lesions in pancreatic ductal adenocarcinoma (PDAC) hijack the epigenetic machinery in stromal components to establish a desmoplastic and therapeutic resistant tumor microenvironment (TME). Here we identify Class I histone deacetylases (HDACs) as key epigenetic factors facilitating the induction of pro-desmoplastic and pro-tumorigenic transcriptional programs in pancreatic stromal fibroblasts. Mechanistically, HDAC-mediated changes in chromatin architecture enable the activation of pro-desmoplastic programs directed by serum response factor (SRF) and forkhead box M1 (FOXM1). HDACs also coordinate fibroblast pro-inflammatory programs inducing leukemia inhibitory factor (LIF) expression, supporting paracrine pro-tumorigenic crosstalk. HDAC depletion in cancer-associated fibroblasts (CAFs) and treatment with the HDAC inhibitor entinostat (Ent) in PDAC mouse models reduce stromal activation and curb tumor progression. Notably, HDAC inhibition (HDACi) enriches a lipogenic fibroblast subpopulation, a potential precursor for myofibroblasts in the PDAC stroma. Overall, our study reveals the stromal targeting potential of HDACi, highlighting the utility of this epigenetic modulating approach in PDAC therapeutics.
RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy in need of new therapeutic options. Using unbiased analyses of super-enhancers (SEs) as sentinels of core genes involved in cell-specific function, here we uncover a druggable SE-mediated RNA-binding protein (RBP) cascade that supports PDAC growth through enhanced mRNA translation. This cascade is driven by a SE associated with the RBP heterogeneous nuclear ribonucleoprotein F, which stabilizes protein arginine methyltransferase 1 (PRMT1) to, in turn, control the translational mediator ubiquitin-associated protein 2-like. All three of these genes and the regulatory SE are essential for PDAC growth and coordinately regulated by the Myc oncogene. In line with this, modulation of the RBP network by PRMT1 inhibition reveals a unique vulnerability in Myc-high PDAC patient organoids and markedly reduces tumor growth in male mice. Our study highlights a functional link between epigenetic regulation and mRNA translation and identifies components that comprise unexpected therapeutic targets for PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Masculino , Animales , Ratones , ARN , Epigénesis Genética , Secuencias Reguladoras de Ácidos Nucleicos , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Metiltransferasas , Proteínas de Unión al ARN/genéticaRESUMEN
BACKGROUND: Solid tumors such as pancreatic ductal adenocarcinoma (PDAC) comprise not just tumor cells but also a microenvironment with which the tumor cells constantly interact. Detailed characterization of the cellular composition of the tumor microenvironment is critical to the understanding of the disease and treatment of the patient. Single-cell transcriptomics has been used to study the cellular composition of different solid tumor types including PDAC. However, almost all of those studies used primary tumor tissues. METHODS: In this study, we employed a single-cell RNA sequencing technology to profile the transcriptomes of individual cells from dissociated primary tumors or metastatic biopsies obtained from patients with PDAC. Unsupervised clustering analysis as well as a new supervised classification algorithm, SuperCT, was used to identify the different cell types within the tumor tissues. The expression signatures of the different cell types were then compared between primary tumors and metastatic biopsies. The expressions of the cell type-specific signature genes were also correlated with patient survival using public datasets. RESULTS: Our single-cell RNA sequencing analysis revealed distinct cell types in primary and metastatic PDAC tissues including tumor cells, endothelial cells, cancer-associated fibroblasts (CAFs), and immune cells. The cancer cells showed high inter-patient heterogeneity, whereas the stromal cells were more homogenous across patients. Immune infiltration varies significantly from patient to patient with majority of the immune cells being macrophages and exhausted lymphocytes. We found that the tumor cellular composition was an important factor in defining the PDAC subtypes. Furthermore, the expression levels of cell type-specific markers for EMT+ cancer cells, activated CAFs, and endothelial cells significantly associated with patient survival. CONCLUSIONS: Taken together, our work identifies significant heterogeneity in cellular compositions of PDAC tumors and between primary tumors and metastatic lesions. Furthermore, the cellular composition was an important factor in defining PDAC subtypes and significantly correlated with patient outcome. These findings provide valuable insights on the PDAC microenvironment and could potentially inform the management of PDAC patients.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Perfilación de la Expresión Génica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Análisis de la Célula Individual , Transcriptoma , Carcinoma Ductal Pancreático/mortalidad , Línea Celular Tumoral , Biología Computacional , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Heterogeneidad Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Neoplasias Pancreáticas/mortalidad , Pronóstico , Análisis de la Célula Individual/métodos , Células del Estroma/metabolismo , Microambiente Tumoral/genética , Neoplasias PancreáticasRESUMEN
Microsatellite instability (MSI) testing is used to screen for Lynch syndrome. The current technique for MSI determination requires DNA from normal and neoplastic tissue and is expensive and laborious. Five quasi-monomorphic markers (NR-21, BAT-25, MONO-27, NR-24, and BAT-26) are included in the Promega MSI analysis kit. With the working hypothesis that this 5-marker panel can accurately determine the MSI status of colorectal tumors without using paired control DNA, we evaluated 478 colorectal tumors and divided them into a test group (N=172, colorectal adenocarcinomas) and a validation group (N=306 including 179 colorectal adenocarcinomas and 127 adenomas). The quasi-monomorphic variation range of each marker was generated from the test group (172 normal samples) and used as a reference value in the subsequent interpretation of MSI status in the test and validation groups. Considering the MSI result using a 5-marker panel with paired control DNA as the gold standard, we identified 136 microsatellite stable (MSS) and 36 microsatellite instability-high (MSI-H) colorectal tumors in the test group and 259 MSS and 47 MSI-H colorectal tumors in the validation group. Using the quasi-monomorphic variation range of each marker rather than paired normal DNA, the 5-marker panel identified all MSI-H colorectal tumors in the test and validation groups, when MSI-H was defined as ≥2 unstable markers. Our study demonstrates that the 5-marker panel within a multiplex polymerase chain reaction of the Promega MSI analysis kit accurately identifies all MSI-H and 95.2% MSS colorectal tumors without using paired normal DNA.
Asunto(s)
Adenocarcinoma/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Inestabilidad de Microsatélites , ADN de Neoplasias/análisis , Marcadores Genéticos , Humanos , Reacción en Cadena de la Polimerasa MultiplexAsunto(s)
Reordenamiento Génico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bandeo Cromosómico , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 8 , Resultado Fatal , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológicoRESUMEN
Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/ BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.
Asunto(s)
Transformación Celular Neoplásica/genética , Reordenamiento Génico , Genes myc , Linfoma Folicular/genética , Linfoma Inmunoblástico de Células Grandes/genética , Células Plasmáticas/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células de la Médula Ósea/patología , Transformación Celular Neoplásica/patología , Análisis Mutacional de ADN , ADN de Neoplasias/genética , Resultado Fatal , Genes de Inmunoglobulinas , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Linfoma Folicular/tratamiento farmacológico , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Cetuximab and panitumumab are monoclonal antibodies used in the treatment of metastatic colorectal cancer (mCRC) by selectively targeting the epidermal growth factor receptor (EGFR) axis. Studies have shown that mutations in codons 12/13 of exon 2 of the KRAS gene render these therapies ineffective. As a result, the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend KRAS mutation testing in mCRC. Appropriate testing depends on the coordinated efforts of the entire treatment team, including the pathologist, who selects the tumor sample and testing platform as well as interprets and reports results. In addition to describing rationale and methodologies for KRAS mutation testing, the authors also summarize their algorithmic approach and elaborate the potential role of newer molecular biomarkers to predict anti-EGFR resistance in wild-type KRAS tumors.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Algoritmos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Cetuximab , Neoplasias Colorrectales/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Humanos , Panitumumab , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Interdigitating dendritic cell sarcoma (IDCS) is a rare tumor derived from interdigitating dendritic cells. Three cases of IDCS associated with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have been described, but no clonal relationship between the 2 neoplasms was demonstrated. We present a detailed case analysis of a CLL/SLL with metachronous IDCS and demonstrate that these 2 neoplasms are clonally related. The IDCS and CLL cells had trisomy 12 and identical monoclonal immunoglobulin heavy chain gene rearrangements. Analysis of transcription factors with a role in myeloid differentiation demonstrated PU.1 up-regulation and C/EBPalpha down-regulation in IDCS compared with CLL. High-density array comparative genomic hybridization also identified gains in part of chromosome 16q in IDCS. Our study demonstrates for the first time clonal transformation of CLL/SLL into IDCS. This phenomenon may be triggered by alterations in lineage-determining transcription programs, which result in transdifferentiation, coupled with additional oncogenic stimuli caused by chromosomal imbalances.
Asunto(s)
Transformación Celular Neoplásica/patología , Sarcoma de Células Dendríticas Interdigitantes/patología , Leucemia Linfocítica Crónica de Células B/patología , Neoplasias Primarias Múltiples , Anciano , Células de la Médula Ósea/química , Células de la Médula Ósea/patología , Transdiferenciación Celular , Transformación Celular Neoplásica/genética , Cromosomas Humanos Par 12 , Células Clonales , Sarcoma de Células Dendríticas Interdigitantes/genética , Reordenamiento Génico de Cadena Pesada de Linfocito B/genética , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Ganglios Linfáticos/química , Ganglios Linfáticos/patología , Masculino , ARN Neoplásico/análisis , TrisomíaAsunto(s)
Neoplasias del Apéndice/patología , Apendicitis/diagnóstico , Enfermedad de Hodgkin/patología , Dolor Abdominal/diagnóstico , Dolor Abdominal/etiología , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Apendicectomía/métodos , Neoplasias del Apéndice/terapia , Apendicitis/cirugía , Biopsia con Aguja , Quimioterapia Adyuvante , Diagnóstico Diferencial , Estudios de Seguimiento , Enfermedad de Hodgkin/terapia , Humanos , Inmunohistoquímica , Linfocitos/patología , Masculino , Tomografía de Emisión de Positrones , Enfermedades Raras , Rituximab , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Bronchus-associated lymphoid tissue lymphoma is a rare disease. It is the most common form of primary pulmonary lymphoma but accounts for less than 1% of all non-Hodgkin's lymphomas. We describe a 67-year-old man who, despite successful treatment of active miliary tuberculosis, developed progression of a concomitant bronchus-associated lymphoid tissue lymphoma. This case is in contrast to previous reports of gastrointestinal-mucosa-associated lymphoid tissue lymphomas and bronchus-associated lymphoid tissue lymphomas, in which treatment of the precipitating antigenic stimulus lead to remission of the lymphoma.
Asunto(s)
Bronquios/patología , Tejido Linfoide/patología , Linfoma , Mycobacterium tuberculosis , Anciano , Humanos , Linfoma no Hodgkin , Masculino , Radiografía TorácicaRESUMEN
CONTEXT: Placental mesenchymal dysplasia is characterized by placentomegaly and may be mistaken for molar pregnancy both clinically and macroscopically because of the presence of "grapelike vesicles." It may be associated with a completely normal fetus, a fetus with growth restriction, or a fetus with features of Beckwith-Wiedemann syndrome. OBJECTIVE: To review the etiology, molecular pathology, gross and microscopic features, clinical presentation, complications, and differential diagnosis of placental mesenchymal dysplasia. DATA SOURCES: The PubMed and the Medline databases were systematically searched for articles between 1970 and 2006. The following keywords were used: placental mesenchymal dysplasia, mesenchymal hyperplasia, molar pregnancy, pseudomolar pregnancy, Beckwith-Wiedemann syndrome, and placentomegaly. Relevant references from review articles were also searched. CONCLUSIONS: Placental mesenchymal dysplasia should be considered in the differential diagnosis when the ultrasonographic findings show a cystic placenta. Close attention should be paid to fetal morphology for early recognition of fetal complications and to prevent unnecessary termination of pregnancy in cases associated with a normal fetus.