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1.
Adv Exp Med Biol ; 1287: 1-7, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034022

RESUMEN

The evolutionary conserved Notch pathway that first developed in metazoans and that was first discovered in fruit flies (Drosophila melanogaster) governs fundamental cell fate decisions and many other cellular key processes not only in embryonic development but also during initiation, promotion, and progression of cancer. On a first look, the Notch pathway appears remarkably simple, with its key feature representing a direct connection between an extracellular signal and transcriptional output without the need of a long chain of protein intermediaries as known from many other signaling pathways. However, on a second, closer look, this obvious simplicity exerts surprising complexity. There is no doubt that the enormous scientific progress in unraveling the functional mechanisms that underlie this complexity has recently greatly increased our knowledge about the role of Notch signaling for pathogenesis and progression of many types of cancer. Moreover, these new scientific findings have shown promise in opening new avenues for cancer prevention and therapy, although this goal is still challenging. Vol. III of the second edition of the book Notch Signaling in Embryology and Cancer, entitled Notch Signaling in Cancer, summarizes important recent developments in this fast-moving and fascinating field. Here, we give an introduction to this book and a short summary of the individual chapters that are written by leading scientists, covering the latest developments in this intriguing research area.


Asunto(s)
Neoplasias/prevención & control , Neoplasias/terapia , Receptores Notch/metabolismo , Transducción de Señal , Animales , Diferenciación Celular , Humanos , Neoplasias/patología
2.
Adv Exp Med Biol ; 1287: 169-181, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33034032

RESUMEN

The Notch signaling pathway controls normal embryonic development and tissue homeostasis of many cell types. It regulates cell proliferation, fate, differentiation, and cell death by short-range signaling between nearby cells that come in contact. The Notch pathway has also been critically involved in the pathobiology of a variety of malignancies, regulating cancer initiation and development, as well as early stages of cancer progression, by adjusting conserved cellular programs. Fibroblasts, an essential for tumor growth component of stroma, have also been affected by Notch regulation. Sequencing Notch gene mutations have been identified in a number of human tumors, revealing information on the progression of specific cancer types, such as ovarian cancer and melanoma, immune-associated tumors such as myeloid neoplasms, but especially in lymphocytic leukemia. Activation of the Notch can be either oncogenic or it may contain growth-suppressive functions, acting as a tumor suppressor in other hematopoietic cells, hepatocytes, skin, and pancreatic epithelium.


Asunto(s)
Progresión de la Enfermedad , Neoplasias/patología , Receptores Notch , Transducción de Señal , Genes Supresores de Tumor , Humanos , Neoplasias/genética , Oncogenes , Receptores Notch/metabolismo
3.
Nat Commun ; 11(1): 4931, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-33004795

RESUMEN

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.


Asunto(s)
Antígenos de Neoplasias/ultraestructura , Proteínas de Neoplasias/ultraestructura , Neoplasias/tratamiento farmacológico , Ubiquitina-Proteína Ligasas/metabolismo , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Secuencias de Aminoácidos , Aminoquinolinas/farmacología , Aminoquinolinas/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinogénesis/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HEK293 , Células HeLa , Ensayos Analíticos de Alto Rendimiento , Humanos , Mutagénesis , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patología , Prueba de Estudio Conceptual , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Dominios Proteicos/genética , Mapeo de Interacción de Proteínas , Relación Estructura-Actividad , Especificidad por Sustrato/efectos de los fármacos , Especificidad por Sustrato/genética , Ubiquitinación/efectos de los fármacos , Ubiquitinación/genética
4.
Nat Commun ; 11(1): 4979, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020468

RESUMEN

Cellular senescence is a known driver of carcinogenesis and age-related diseases, yet senescence is required for various physiological processes. However, the mechanisms and factors that control the negative effects of senescence while retaining its benefits are still elusive. Here, we show that the rasGAP SH3-binding protein 1 (G3BP1) is required for the activation of the senescent-associated secretory phenotype (SASP). During senescence, G3BP1 achieves this effect by promoting the association of the cyclic GMP-AMP synthase (cGAS) with cytosolic chromatin fragments. In turn, G3BP1, through cGAS, activates the NF-κB and STAT3 pathways, promoting SASP expression and secretion. G3BP1 depletion or pharmacological inhibition impairs the cGAS-pathway preventing the expression of SASP factors without affecting cell commitment to senescence. These SASPless senescent cells impair senescence-mediated growth of cancer cells in vitro and tumor growth in vivo. Our data reveal that G3BP1 is required for SASP expression and that SASP secretion is a primary mediator of senescence-associated tumor growth.


Asunto(s)
Senescencia Celular/fisiología , ADN Helicasas/metabolismo , Neoplasias/patología , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Células A549 , Animales , Carcinogénesis , Línea Celular , Movimiento Celular , Citocinas/metabolismo , ADN Helicasas/antagonistas & inhibidores , ADN Helicasas/deficiencia , Humanos , Inflamación , Ratones , Neoplasias/metabolismo , Nucleotidiltransferasas/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/deficiencia , ARN Helicasas/antagonistas & inhibidores , ARN Helicasas/deficiencia , Proteínas con Motivos de Reconocimiento de ARN/antagonistas & inhibidores , Proteínas con Motivos de Reconocimiento de ARN/deficiencia , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/metabolismo
5.
Nat Commun ; 11(1): 4980, 2020 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-33020477

RESUMEN

The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as "Yin and Yang" partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.


Asunto(s)
Neoplasias/patología , Proteínas Proto-Oncogénicas c-myc/metabolismo , ARN Largo no Codificante/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Carcinogénesis , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/genética , ARN Largo no Codificante/genética , Sumoilación , Proteína p53 Supresora de Tumor/genética , Ubiquitinación
6.
Yakugaku Zasshi ; 140(10): 1243-1249, 2020.
Artículo en Japonés | MEDLINE | ID: mdl-32999203

RESUMEN

Here the author describes the tumor-selective delivery of a fluorescence photosensitizing agent and an antitumor agent, based on the polymer effect of an N-(2-hydroxypropyl)methacrylamide (HPMA) based copolymer, by utilizing the enhanced permeability and retention (EPR) effect seen in solid tumors. Firstly, the tumor distribution of the photosensitizer, zinc-protoporphyrin IX (ZnPP), was significantly increased by conjugation with the HPMA polymer (P-ZnPP). The P-ZnPP suppressed tumor growth by local generation of cytotoxic singlet oxygen, and the tumor tissue was visualized by fluorescence upon light irradiation. Subsequently, a two-step mechanism for tumor selectivity was observed for the cytotoxic anthracycline, pirarubicin (THP), which conjugated the HPMA-based copolymer via a hydrazone bond (P-THP). The EPR-dependent accumulation of P-THP and the tumor-selective release of THP in the tumor tissues led to highly tumor-selective toxicity. Rapid cell uptake of THP compared to other anthracyclines, and deeper P-THP penetration of the tumor cell spheroid were attributed to the superior antitumor activity of P-THP. The molecular weight of P-THP affected its antitumor activity; oligomeric P-THP derivatives with higher molecular weights, DP-THP and SP-THP, showed even higher antitumor activity. P-THP was effective for both implanted tumor and autochthonous tumor models. These results indicate that nano-sized anticancer drugs based on polymer effect are promising clinical therapeutics.


Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Desarrollo de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Fármacos Fotosensibilizantes , Polímeros , Protoporfirinas , Animales , Antraciclinas/química , Antraciclinas/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/química , Doxorrubicina/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Metacrilatos/química , Terapia Molecular Dirigida , Peso Molecular , Neoplasias/patología , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo
7.
Molecules ; 25(19)2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33050063

RESUMEN

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian Iris sp. (Iris pallida, Iris hungarica, Iris sibirica, and Iris variegata) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3',5'-tetramethoxyisoflavone, irisolidone-7-O-ß-d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. I. hungarica and I. variegata showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of I. variegata (7.089 ± 0.032 mg/g) and I. hungarica (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r2 > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied Iris sp. I. hungarica and I. variegata rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined Iris sp.


Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Antioxidantes/farmacología , Antivirales/farmacología , Iris (Planta)/química , Extractos Vegetales/farmacología , Coronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Células Tumorales Cultivadas
8.
Nat Commun ; 11(1): 5060, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033246

RESUMEN

Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.


Asunto(s)
Sistemas CRISPR-Cas/genética , Neoplasias/genética , Fusión de Oncogenes/genética , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Doxorrubicina/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Eliminación de Gen , Sitios Genéticos , Inestabilidad Genómica , Células HEK293 , Humanos , Intrones/genética , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Proteínas de Fusión Oncogénica/genética , ARN Guia/metabolismo , Reproducibilidad de los Resultados , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Tumour Biol ; 42(10): 1010428320965284, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33028168

RESUMEN

Glucose, as the main consuming nutrient of the body, faces different destinies in cancer cells. Glycolysis, oxidative phosphorylation, and pentose phosphate pathways produce different glucose-derived metabolites and thus affect cells' bioenergetics differently. Tumor cells' dependency to aerobic glycolysis and other cancer-specific metabolism changes are known as the cancer hallmarks, distinct cancer cells from normal cells. Therefore, these tumor-specific characteristics receive the limelight as targets for cancer therapy. Glutamine, serine, and fatty acid oxidation together with 5-lipoxygenase are main pathways that have attracted lots of attention for cancer therapy. In this review, we not only discuss different tumor metabolism aspects but also discuss the metabolism roles in the promotion of cancer cells at different stages and their difference with normal cells. Besides, we dissect the inhibitors potential in blocking the main metabolic pathways to introduce the effective and non-effective inhibitors in the field.


Asunto(s)
Antineoplásicos/uso terapéutico , Metabolismo Energético/efectos de los fármacos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Medicina de Precisión , Antineoplásicos/farmacología , Ciclo del Ácido Cítrico/efectos de los fármacos , Metabolismo Energético/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Glucólisis/efectos de los fármacos , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias/etiología , Neoplasias/patología , Fosforilación Oxidativa/efectos de los fármacos , Vía de Pentosa Fosfato/efectos de los fármacos , Medicina de Precisión/métodos
10.
Cancer Sci ; 111(10): 3468-3477, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33044028

RESUMEN

The effectiveness of current chemotherapies for cancer is gradually progressing; however achieving a complete cure through chemotherapy is still difficult and has been the main goal in treatment of advanced cancer. Drug resistance is an issue in cancer therapy, therefore increasing numbers of investigations into drug resistance have focused on the characteristics of the cancer cells themselves. The interaction between the tumor microenvironment (TME) and cancer cells is also intimately involved in the development of drug resistance. Cancer-associated fibroblasts (CAFs) are a predominant component of the TME and affect tumor progression by secreting soluble factors. This review summarizes the most up-to-date knowledge of CAFs and drug resistance in cancer, with a focus on factors secreted from CAFs including proteins, cytokines, extracellular vesicles, and metabolites. A perspective on the potential role of anti-CAF therapies in overcoming CAF-induced drug resistance is also discussed.


Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Resistencia a Medicamentos , Neoplasias/tratamiento farmacológico , Humanos , Neoplasias/patología , Microambiente Tumoral
11.
BMC Bioinformatics ; 21(1): 377, 2020 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-32883200

RESUMEN

BACKGROUND: A large number of experimental studies show that the mutation and regulation of long non-coding RNAs (lncRNAs) are associated with various human diseases. Accurate prediction of lncRNA-disease associations can provide a new perspective for the diagnosis and treatment of diseases. The main function of many lncRNAs is still unclear and using traditional experiments to detect lncRNA-disease associations is time-consuming. RESULTS: In this paper, we develop a novel and effective method for the prediction of lncRNA-disease associations using network feature similarity and gradient boosting (LDNFSGB). In LDNFSGB, we first construct a comprehensive feature vector to effectively extract the global and local information of lncRNAs and diseases through considering the disease semantic similarity (DISSS), the lncRNA function similarity (LNCFS), the lncRNA Gaussian interaction profile kernel similarity (LNCGS), the disease Gaussian interaction profile kernel similarity (DISGS), and the lncRNA-disease interaction (LNCDIS). Particularly, two methods are used to calculate the DISSS (LNCFS) for considering the local and global information of disease semantics (lncRNA functions) respectively. An autoencoder is then used to reduce the dimensionality of the feature vector to obtain the optimal feature parameter from the original feature set. Furthermore, we employ the gradient boosting algorithm to obtain the lncRNA-disease association prediction. CONCLUSIONS: In this study, hold-out, leave-one-out cross-validation, and ten-fold cross-validation methods are implemented on three publicly available datasets to evaluate the performance of LDNFSGB. Extensive experiments show that LDNFSGB dramatically outperforms other state-of-the-art methods. The case studies on six diseases, including cancers and non-cancers, further demonstrate the effectiveness of our method in real-world applications.


Asunto(s)
Algoritmos , Neoplasias/patología , ARN Largo no Codificante/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Área Bajo la Curva , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/patología , Humanos , Neoplasias/genética , ARN Largo no Codificante/genética , Curva ROC
13.
J Immunother Cancer ; 8(2)2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32895296

RESUMEN

BACKGROUND: Individualized prediction of mortality risk can inform the treatment strategy for patients with COVID-19 and solid tumors and potentially improve patient outcomes. We aimed to develop a nomogram for predicting in-hospital mortality of patients with COVID-19 with solid tumors. METHODS: We enrolled patients with COVID-19 with solid tumors admitted to 32 hospitals in China between December 17, 2020, and March 18, 2020. A multivariate logistic regression model was constructed via stepwise regression analysis, and a nomogram was subsequently developed based on the fitted multivariate logistic regression model. Discrimination and calibration of the nomogram were evaluated by estimating the area under the receiver operator characteristic curve (AUC) for the model and by bootstrap resampling, a Hosmer-Lemeshow test, and visual inspection of the calibration curve. RESULTS: There were 216 patients with COVID-19 with solid tumors included in the present study, of whom 37 (17%) died and the other 179 all recovered from COVID-19 and were discharged. The median age of the enrolled patients was 63.0 years and 113 (52.3%) were men. Multivariate logistic regression revealed that increasing age (OR=1.08, 95% CI 1.00 to 1.16), receipt of antitumor treatment within 3 months before COVID-19 (OR=28.65, 95% CI 3.54 to 231.97), peripheral white blood cell (WBC) count ≥6.93 ×109/L (OR=14.52, 95% CI 2.45 to 86.14), derived neutrophil-to-lymphocyte ratio (dNLR; neutrophil count/(WBC count minus neutrophil count)) ≥4.19 (OR=18.99, 95% CI 3.58 to 100.65), and dyspnea on admission (OR=20.38, 95% CI 3.55 to 117.02) were associated with elevated mortality risk. The performance of the established nomogram was satisfactory, with an AUC of 0.953 (95% CI 0.908 to 0.997) for the model, non-significant findings on the Hosmer-Lemeshow test, and rough agreement between predicted and observed probabilities as suggested in calibration curves. The sensitivity and specificity of the model were 86.4% and 92.5%. CONCLUSION: Increasing age, receipt of antitumor treatment within 3 months before COVID-19 diagnosis, elevated WBC count and dNLR, and having dyspnea on admission were independent risk factors for mortality among patients with COVID-19 and solid tumors. The nomogram based on these factors accurately predicted mortality risk for individual patients.


Asunto(s)
Infecciones por Coronavirus/mortalidad , Mortalidad Hospitalaria , Neoplasias/terapia , Nomogramas , Neumonía Viral/mortalidad , Factores de Edad , Anciano , Área Bajo la Curva , Betacoronavirus , China/epidemiología , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/fisiopatología , Disnea/fisiopatología , Fatiga/fisiopatología , Femenino , Frecuencia Cardíaca , Humanos , Recuento de Leucocitos , Modelos Logísticos , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/terapia , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Neoplasias/complicaciones , Neoplasias/patología , Neutrófilos , Pandemias , Neumonía Viral/sangre , Neumonía Viral/complicaciones , Neumonía Viral/fisiopatología , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Curva ROC , Estudios Retrospectivos , Medición de Riesgo
14.
Nat Commun ; 11(1): 4469, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32901013

RESUMEN

Dissecting tumor heterogeneity is a key to understanding the complex mechanisms underlying drug resistance in cancers. The rich literature of pioneering studies on tumor heterogeneity analysis spurred a recent community-wide benchmark study that compares diverse modeling algorithms. Here we present FastClone, a top-performing algorithm in accuracy in this benchmark. FastClone improves over existing methods by allowing the deconvolution of subclones that have independent copy number variation events within the same chromosome regions. We characterize the behavior of FastClone in identifying subclones using stage III colon cancer primary tumor samples as well as simulated data. It achieves approximately 100-fold acceleration in computation for both simulated and patient data. The efficacy of FastClone will allow its application to large-scale data and clinical data, and facilitate personalized medicine in cancers.


Asunto(s)
Algoritmos , Variaciones en el Número de Copia de ADN , Neoplasias/genética , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Biología Computacional/métodos , Simulación por Computador , ADN de Neoplasias/genética , Resistencia a Antineoplásicos/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Modelos Genéticos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Filogenia , Medicina de Precisión , Análisis de Secuencia de ADN
15.
Nat Commun ; 11(1): 4534, 2020 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-32913330

RESUMEN

Collisions between the DNA replication machinery and co-transcriptional R-loops can impede DNA synthesis and are a major source of genomic instability in cancer cells. How cancer cells deal with R-loops to proliferate is poorly understood. Here we show that the ATP-dependent chromatin remodelling INO80 complex promotes resolution of R-loops to prevent replication-associated DNA damage in cancer cells. Depletion of INO80 in prostate cancer PC3 cells leads to increased R-loops. Overexpression of the RNA:DNA endonuclease RNAse H1 rescues the DNA synthesis defects and suppresses DNA damage caused by INO80 depletion. R-loops co-localize with and promote recruitment of INO80 to chromatin. Artificial tethering of INO80 to a LacO locus enabled turnover of R-loops in cis. Finally, counteracting R-loops by INO80 promotes proliferation and averts DNA damage-induced death in cancer cells. Our work suggests that INO80-dependent resolution of R-loops promotes DNA replication in the presence of transcription, thus enabling unlimited proliferation in cancers.


Asunto(s)
ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Proliferación Celular/genética , Replicación del ADN , Proteínas de Unión al ADN/metabolismo , Neoplasias/genética , Estructuras R-Loop/genética , Apoptosis/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Ensamble y Desensamble de Cromatina , Daño del ADN , Inestabilidad Genómica , Humanos , Neoplasias/patología , Transcripción Genética
16.
Nat Commun ; 11(1): 4545, 2020 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917858

RESUMEN

TGF-ß1, ß2 and ß3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARP:TGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-ß1/PD-1 blockade are immune-mediated, do not require FcγR-dependent functions and increase effector functions of anti-tumor CD8+ T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.


Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas de la Membrana/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Animales , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral/trasplante , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/inmunología , Células HEK293 , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Neoplasias/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo
17.
Medicine (Baltimore) ; 99(37): e22153, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32925773

RESUMEN

BACKGROUND: Immune checkpoint blockade (ICB) brings hope to many late-stage cancer patients yet its marker for response remains elusive. METHODS: We developed a hypothesis that treatment-related adverse events (TrAEs) could predict objective response rate (ORR) to ICB. We plotted ORR against corresponding any and grade 3 to 5 (G3-5) TrAEs across a variety of cancer types by performing a meta-analysis using linear regression. RESULTS: We identified 113 eligible studies encompassing 25 types of malignancies that were treated with ICB or ICB-based regimes. A significant linear correlation was observed for any and severe TrAEs, respectively. The correlation coefficient was 0.57 (r = 0.324) for any TrAE and 0.61 (r = 0.37) for G3-5 TrAE. For melanoma, the correlation coefficient was 0.81 (r = 0.57) for any TrAE and 0.65 (r = 0.42) for G3-5 TrAEs. For RCC, the correlation coefficient was 0.86 (r = 0.74) for any TrAE and 0.91 (r = 0.83) for G3-5 TrAE. For NSCLC, the correlation coefficient was 0.55 (r = 0.3) for any TrAE and 0.74 (r = 0.86) for G3-5 TrAE. For UC, the correlation coefficient was 0.47 (r = 0.68) for any TrAE and 0.27 (r = 0.52) for G3-5 TrAE, yet the correlation was insignificant for severe AEs. CONCLUSION: Our findings suggest that over half of ICB responses could be reflected by any adverse events and ∼60% of responses could be reflected by severe AEs. Further validation is needed in individual trials.


Asunto(s)
Antineoplásicos Inmunológicos/efectos adversos , Neoplasias/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno CTLA-4/antagonistas & inhibidores , Humanos , Estadificación de Neoplasias , Neoplasias/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Análisis de Supervivencia , Resultado del Tratamiento
18.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32888471

RESUMEN

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Inmunoterapia/efectos adversos , Inflamación/terapia , Neoplasias/terapia , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/inmunología , Ensayos Clínicos como Asunto , Humanos , Inmunidad Celular/inmunología , Inflamación/inmunología , Inflamación/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología
19.
Nat Commun ; 11(1): 4370, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32873792

RESUMEN

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAFV600E signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Sitio Alostérico/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Imidazoles/farmacología , Imidazoles/uso terapéutico , Sistema de Señalización de MAP Quinasas/genética , Simulación del Acoplamiento Molecular , Mutación , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Multimerización de Proteína/efectos de los fármacos , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/ultraestructura , Piridazinas/farmacología , Piridazinas/uso terapéutico , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad
20.
Nat Commun ; 11(1): 4391, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32873806

RESUMEN

Deep learning with Convolutional Neural Networks has shown great promise in image-based classification and enhancement but is often unsuitable for predictive modeling using features without spatial correlations. We present a feature representation approach termed REFINED (REpresentation of Features as Images with NEighborhood Dependencies) to arrange high-dimensional vectors in a compact image form conducible for CNN-based deep learning. We consider the similarities between features to generate a concise feature map in the form of a two-dimensional image by minimizing the pairwise distance values following a Bayesian Metric Multidimensional Scaling Approach. We hypothesize that this approach enables embedded feature extraction and, integrated with CNN-based deep learning, can boost the predictive accuracy. We illustrate the superior predictive capabilities of the proposed framework as compared to state-of-the-art methodologies in drug sensitivity prediction scenarios using synthetic datasets, drug chemical descriptors as predictors from NCI60, and both transcriptomic information and drug descriptors as predictors from GDSC.


Asunto(s)
Antineoplásicos/farmacología , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Teorema de Bayes , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias/patología , Análisis de Secuencia por Matrices de Oligonucleótidos
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