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1.
Genome Res ; 2022 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-35760562

RESUMEN

The advent of massively parallel sequencing revealed extensive transcription beyond protein-coding genes, identifying tens of thousands of long noncoding RNAs (lncRNAs). Selected functional examples raised the possibility that lncRNAs, as a class, may maintain broad regulatory roles. Expression of lncRNAs is strongly linked with adjacent protein-coding gene expression, suggesting potential cis-regulatory functions. A more detailed understanding of these regulatory roles may be obtained through careful examination of the precise timing of lncRNA expression relative to adjacent protein-coding genes. Despite the diversity of reported lncRNA regulatory mechanisms, where causal cis-regulatory relationships exist, lncRNA transcription is expected to precede changes in target gene expression. Using a high temporal resolution RNA-seq time course, we profiled the expression dynamics of several thousand lncRNAs and protein-coding genes in synchronized, transitioning human cells. Our findings reveal that lncRNAs are expressed synchronously with adjacent protein-coding genes. Analysis of lipopolysaccharide-activated mouse dendritic cells revealed the same temporal relationship observed in transitioning human cells. Our findings suggest broad-scale cis-regulatory roles for lncRNAs are not common. The strong association between lncRNAs and adjacent genes may instead indicate an origin as transcriptional by-products from active protein-coding gene promoters and enhancers.

2.
Trends Immunol ; 40(2): 142-158, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30639050

RESUMEN

Immune 'checkpoint' inhibitors can increase the activity of tumor-resident cytotoxic lymphocytes and have revolutionized cancer treatment. Current therapies block inhibitory pathways in tumor-infiltrating CD8+ T cells and recent studies have shown similar programs in other effector populations such as natural killer (NK) cells. NK cells are critical for immunosurveillance, particularly the control of metastatic cells or hematological cancers. However, how NK cells specifically recognize transformed cells and dominant negative feedback pathways, as well as how tumors escape NK cell control, remains undefined. This review summarizes recent advances that have illuminated inhibitory checkpoints in NK cells, some of which are shared with conventional cytotoxic T lymphocytes. It also outlines emerging approaches aimed at unleashing the potential of NK cells in immunotherapy.


Asunto(s)
Inmunoterapia , Células Asesinas Naturales/inmunología , Neoplasias/terapia , Animales , Humanos , Células Asesinas Naturales/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/patología , Linfocitos T Citotóxicos/inmunología
3.
PLoS Comput Biol ; 17(10): e1009513, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34644304

RESUMEN

It is widely acknowledged that the construction of large-scale dynamic models in systems biology requires complex modelling problems to be broken up into more manageable pieces. To this end, both modelling and software frameworks are required to enable modular modelling. While there has been consistent progress in the development of software tools to enhance model reusability, there has been a relative lack of consideration for how underlying biophysical principles can be applied to this space. Bond graphs combine the aspects of both modularity and physics-based modelling. In this paper, we argue that bond graphs are compatible with recent developments in modularity and abstraction in systems biology, and are thus a desirable framework for constructing large-scale models. We use two examples to illustrate the utility of bond graphs in this context: a model of a mitogen-activated protein kinase (MAPK) cascade to illustrate the reusability of modules and a model of glycolysis to illustrate the ability to modify the model granularity.


Asunto(s)
Modelos Biológicos , Biología de Sistemas/métodos , Animales , Sistema de Señalización de MAP Quinasas/fisiología , Xenopus
4.
Nucleic Acids Res ; 48(19): e113, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-32997146

RESUMEN

Gene expression signatures have been critical in defining the molecular phenotypes of cells, tissues, and patient samples. Their most notable and widespread clinical application is stratification of breast cancer patients into molecular (PAM50) subtypes. The cost and relatively large amounts of fresh starting material required for whole-transcriptome sequencing has limited clinical application of thousands of existing gene signatures captured in repositories such as the Molecular Signature Database. We identified genes with stable expression across a range of abundances, and with a preserved relative ordering across thousands of samples, allowing signature scoring and supporting general data normalisation for transcriptomic data. Our new method, stingscore, quantifies and summarises relative expression levels of signature genes from individual samples through the inclusion of these 'stably-expressed genes'. We show that our list of stable genes has better stability across cancer and normal tissue data than previously proposed gene sets. Additionally, we show that signature scores computed from targeted transcript measurements using stingscore can predict docetaxel response in breast cancer patients. This new approach to gene expression signature analysis will facilitate the development of panel-type tests for gene expression signatures, thus supporting clinical translation of the powerful insights gained from cancer transcriptomic studies.


Asunto(s)
Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica/métodos , Neoplasias/genética , Transcriptoma , Humanos
5.
Nucleic Acids Res ; 47(16): 8606-8619, 2019 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-31372646

RESUMEN

Epithelial-mesenchymal transition (EMT) has been a subject of intense scrutiny as it facilitates metastasis and alters drug sensitivity. Although EMT-regulatory roles for numerous miRNAs and transcription factors are known, their functions can be difficult to disentangle, in part due to the difficulty in identifying direct miRNA targets from complex datasets and in deciding how to incorporate 'indirect' miRNA effects that may, or may not, represent biologically relevant information. To better understand how miRNAs exert effects throughout the transcriptome during EMT, we employed Exon-Intron Split Analysis (EISA), a bioinformatic technique that separates transcriptional and post-transcriptional effects through the separate analysis of RNA-Seq reads mapping to exons and introns. We find that in response to the manipulation of miRNAs, a major effect on gene expression is transcriptional. We also find extensive co-ordination of transcriptional and post-transcriptional regulatory mechanisms during both EMT and mesenchymal to epithelial transition (MET) in response to TGF-ß or miR-200c respectively. The prominent transcriptional influence of miRNAs was also observed in other datasets where miRNA levels were perturbed. This work cautions against a narrow approach that is limited to the analysis of direct targets, and demonstrates the utility of EISA to examine complex regulatory networks involving both transcriptional and post-transcriptional mechanisms.


Asunto(s)
Transición Epitelial-Mesenquimal/genética , Redes Reguladoras de Genes , MicroARNs/genética , Procesamiento Postranscripcional del ARN , ARN Mensajero/genética , Transcripción Genética , Línea Celular , Biología Computacional/métodos , Conjuntos de Datos como Asunto , Factor de Crecimiento Epidérmico/farmacología , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exones , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Intrones , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismo , Transducción de Señal , Transfección , Factor de Crecimiento Transformador beta/farmacología
6.
J Theor Biol ; 481: 10-23, 2019 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-30273576

RESUMEN

Membrane transporters contribute to the regulation of the internal environment of cells by translocating substrates across cell membranes. Like all physical systems, the behaviour of membrane transporters is constrained by the laws of thermodynamics. However, many mathematical models of transporters, especially those incorporated into whole-cell models, are not thermodynamically consistent, leading to unrealistic behaviour. In this paper we use a physics-based modelling framework, in which the transfer of energy is explicitly accounted for, to develop thermodynamically consistent models of transporters. We then apply this methodology to model two specific transporters: the cardiac sarcoplasmic/endoplasmic Ca2+ ATPase (SERCA) and the cardiac Na+/K+ ATPase.


Asunto(s)
Membrana Celular/enzimología , Modelos Químicos , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/química , Termodinámica , Animales , Membrana Celular/química , Humanos
7.
BMC Bioinformatics ; 19(1): 404, 2018 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-30400809

RESUMEN

BACKGROUND: Gene set scoring provides a useful approach for quantifying concordance between sample transcriptomes and selected molecular signatures. Most methods use information from all samples to score an individual sample, leading to unstable scores in small data sets and introducing biases from sample composition (e.g. varying numbers of samples for different cancer subtypes). To address these issues, we have developed a truly single sample scoring method, and associated R/Bioconductor package singscore ( https://bioconductor.org/packages/singscore ). RESULTS: We use multiple cancer data sets to compare singscore against widely-used methods, including GSVA, z-score, PLAGE, and ssGSEA. Our approach does not depend upon background samples and scores are thus stable regardless of the composition and number of samples being scored. In contrast, scores obtained by GSVA, z-score, PLAGE and ssGSEA can be unstable when less data are available (NS < 25). The singscore method performs as well as the best performing methods in terms of power, recall, false positive rate and computational time, and provides consistently high and balanced performance across all these criteria. To enhance the impact and utility of our method, we have also included a set of functions implementing visual analysis and diagnostics to support the exploration of molecular phenotypes in single samples and across populations of data. CONCLUSIONS: The singscore method described here functions independent of sample composition in gene expression data and thus it provides stable scores, which are particularly useful for small data sets or data integration. Singscore performs well across all performance criteria, and includes a suite of powerful visualization functions to assist in the interpretation of results. This method performs as well as or better than other scoring approaches in terms of its power to distinguish samples with distinct biology and its ability to call true differential gene sets between two conditions. These scores can be used for dimensional reduction of transcriptomic data and the phenotypic landscapes obtained by scoring samples against multiple molecular signatures may provide insights for sample stratification.


Asunto(s)
Biología Computacional/métodos , Neoplasias/genética , Neoplasias/patología , Fenotipo , Medicina de Precisión , Transcriptoma , Perfilación de la Expresión Génica/métodos , Humanos
8.
Breast Cancer Res ; 18(1): 116, 2016 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-27887631

RESUMEN

Lineage tracing is increasingly being utilised to probe different cell types that exist within the mammary gland. Whilst this technique is powerful for tracking cells in vivo and dissecting the roles of different cellular subsets in development, homeostasis and oncogenesis, there are important caveats associated with lineage tracing strategies. Here we highlight key parameters of particular relevance for the mammary gland. These include tissue preparation for whole-mount imaging, whereby the inclusion of enzymatic digestion can drastically alter tissue architecture and cell morphology, and therefore should be avoided. Other factors include the scoring of clones in three dimensions versus two dimensions, the timing of induction, and the marked variability in labelling efficiency that is evident not only between different mouse models harbouring a similar gene promoter but also within a given strain and even within a single mammary gland. Thus, it becomes crucial to visualise extensive areas of ductal tissue and to consider the intricacies of the methodology for lineage tracing studies on normal mammary development and on potential 'cells of origin' of cancer.


Asunto(s)
Linaje de la Célula , Glándulas Mamarias Animales/diagnóstico por imagen , Glándulas Mamarias Humanas/diagnóstico por imagen , Imagen Molecular , Animales , Biomarcadores , Linaje de la Célula/genética , Rastreo Celular/métodos , Evolución Clonal , Femenino , Humanos , Imagenología Tridimensional/métodos , Imagen Molecular/métodos
9.
Mol Cancer ; 15(1): 72, 2016 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-27852308

RESUMEN

BACKGROUND: In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence. METHODS: We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson's correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines - the Ludwig Melbourne melanoma (LM-MEL) cell line panel - we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies. RESULTS: Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, -221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro. CONCLUSIONS: This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation. Computational scripts are available: http://github.com/uomsystemsbiology/LMMEL-miR-miner.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Melanoma/patología , MicroARNs/genética , Algoritmos , Línea Celular Tumoral , Movimiento Celular/genética , Biología Computacional/métodos , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Humanos , Invasividad Neoplásica , Fenotipo , Interferencia de ARN , Procesamiento Postranscripcional del ARN , Estabilidad del ARN , ARN Mensajero/genética , Transcriptoma , Flujo de Trabajo
10.
Bioinformatics ; 31(2): 277-8, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25246431

RESUMEN

UNLABELLED: The wide variety of published approaches for the problem of regulatory network inference makes using multiple inference algorithms complex and time-consuming. Network Analysis and Inference Library (NAIL) is a set of software tools to simplify the range of computational activities involved in regulatory network inference. It uses a modular approach to connect different network inference algorithms to the same visualization and network-based analyses. NAIL is technology-independent and includes an interface layer to allow easy integration of components into other applications. AVAILABILITY AND IMPLEMENTATION: NAIL is implemented in MATLAB, runs on Windows, Linux and OSX, and is available from SourceForge at https://sourceforge.net/projects/nailsystemsbiology/ for all researchers to use. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Asunto(s)
Gráficos por Computador , Redes Reguladoras de Genes , Programas Informáticos , Biología de Sistemas/métodos , Algoritmos , Humanos
11.
Cell Commun Signal ; 13: 26, 2015 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-25975820

RESUMEN

INTRODUCTION: The normal process of epithelial mesenchymal transition (EMT) is subverted by carcinoma cells to facilitate metastatic spread. Cancer cells rarely undergo a full conversion to the mesenchymal phenotype, and instead adopt positions along the epithelial-mesenchymal axis, a propensity we refer to as epithelial mesenchymal plasticity (EMP). EMP is associated with increased risk of metastasis in breast cancer and consequent poor prognosis. Drivers towards the mesenchymal state in malignant cells include growth factor stimulation or exposure to hypoxic conditions. METHODS: We have examined EMP in two cell line models of breast cancer: the PMC42 system (PMC42-ET and PMC42-LA sublines) and MDA-MB-468 cells. Transition to a mesenchymal phenotype was induced across all three cell lines using epidermal growth factor (EGF) stimulation, and in MDA-MB-468 cells by hypoxia. We used RNA sequencing to identify gene expression changes that occur as cells transition to a more-mesenchymal phenotype, and identified the cell signalling pathways regulated across these experimental systems. We then used inhibitors to modulate signalling through these pathways, verifying the conclusions of our transcriptomic analysis. RESULTS: We found that EGF and hypoxia both drive MDA-MB-468 cells to phenotypically similar mesenchymal states. Comparing the transcriptional response to EGF and hypoxia, we have identified differences in the cellular signalling pathways that mediate, and are influenced by, EMT. Significant differences were observed for a number of important cellular signalling components previously implicated in EMT, such as HBEGF and VEGFA. We have shown that EGF- and hypoxia-induced transitions respond differently to treatment with chemical inhibitors (presented individually and in combinations) in these breast cancer cells. Unexpectedly, MDA-MB-468 cells grown under hypoxic growth conditions became even more mesenchymal following exposure to certain kinase inhibitors that prevent growth-factor induced EMT, including the mTOR inhibitor everolimus and the AKT1/2/3 inhibitor AZD5363. CONCLUSIONS: While resulting in a common phenotype, EGF and hypoxia induced subtly different signalling systems in breast cancer cells. Our findings have important implications for the use of kinase inhibitor-based therapeutic interventions in breast cancers, where these heterogeneous signalling landscapes will influence the therapeutic response.


Asunto(s)
Neoplasias de la Mama/metabolismo , Factor de Crecimiento Epidérmico/farmacología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inmunosupresores/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Transducción de Señal/efectos de los fármacos , Sirolimus/análogos & derivados , Neoplasias de la Mama/patología , Hipoxia de la Célula/efectos de los fármacos , Línea Celular Tumoral , Everolimus , Femenino , Humanos , Metástasis de la Neoplasia , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo
12.
Clin Transl Immunology ; 13(5): e1507, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38707997

RESUMEN

Objectives: Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges. Methods: To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline. Results: We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions. Conclusions: Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility.

13.
PLoS One ; 18(11): e0292278, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37917641

RESUMEN

Drugs targeting cyclin-dependent kinases 4 and 6 (CDK4/6) are promising new treatments for melanoma and other solid malignancies. In studies on CDK4/6 inhibitor resistance, protein arginine methyltransferase 5 (PRMT5) regulation of alternative splicing was shown to be an important downstream component of the CDK4/6 pathway. However, the full effects of inhibition of CDK4/6 on splicing events in melanoma and the extent to which they are dependent on PRMT5 has not been established. We performed full-length mRNA sequencing on CHL1 and A375 melanoma cell lines treated with the CDK4/6 inhibitor palbociclib and the PRMT5 inhibitor GSK3326595 and analysed data for differential gene expression and differential pre-mRNA splicing induced by these agents. Changes in gene expression and RNA splicing were more extensive under PRMT5 inhibition than under CDK4/6 inhibition. Although PRMT5 inhibition and CDK4/6 inhibition induced common RNA splicing events and gene expression profiles, the majority of events induced by CDK4/6 inhibition were distinct. Our findings indicate CDK4/6 has the ability to regulate alternative splicing in a manner that is distinct from PRMT5 inhibition, resulting in divergent changes in gene expression under each therapy.


Asunto(s)
Empalme Alternativo , Melanoma , Humanos , Proteína-Arginina N-Metiltransferasas/metabolismo , Línea Celular Tumoral , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/metabolismo , Empalme del ARN , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo
14.
Clin Epigenetics ; 15(1): 73, 2023 04 29.
Artículo en Inglés | MEDLINE | ID: mdl-37120619

RESUMEN

BACKGROUND: Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation. RESULTS: Using The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration. CONCLUSIONS: By combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Metilación de ADN , Epigénesis Genética , Genes Supresores de Tumor , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica
15.
Adv Sci (Weinh) ; 10(22): e2301802, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37217832

RESUMEN

Epithelial-mesenchymal transition (EMT) is a reversible transcriptional program invoked by cancer cells to drive cancer progression. Transcription factor ZEB1 is a master regulator of EMT, driving disease recurrence in poor-outcome triple negative breast cancers (TNBCs). Here, this work silences ZEB1 in TNBC models by CRISPR/dCas9-mediated epigenetic editing, resulting in highly-specific and nearly complete suppression of ZEB1 in vivo, accompanied by long-lasting tumor inhibition. Integrated "omic" changes promoted by dCas9 linked to the KRAB domain (dCas9-KRAB) enabled the discovery of a ZEB1-dependent-signature of 26 genes differentially-expressed and -methylated, including the reactivation and enhanced chromatin accessibility in cell adhesion loci, outlining epigenetic reprogramming toward a more epithelial state. In the ZEB1 locus transcriptional silencing is associated with induction of locally-spread heterochromatin, significant changes in DNA methylation at specific CpGs, gain of H3K9me3, and a near complete erasure of H3K4me3 in the ZEB1 promoter. Epigenetic shifts induced by ZEB1-silencing are enriched in a subset of human breast tumors, illuminating a clinically-relevant hybrid-like state. Thus, the synthetic epi-silencing of ZEB1 induces stable "lock-in" epigenetic reprogramming of mesenchymal tumors associated with a distinct and stable epigenetic landscape. This work outlines epigenome-engineering approaches for reversing EMT and customizable precision molecular oncology approaches for targeting poor outcome breast cancers.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Recurrencia Local de Neoplasia/genética , Factores de Transcripción/genética , Epigénesis Genética/genética
16.
Cell Chem Biol ; 30(10): 1191-1210.e20, 2023 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-37557181

RESUMEN

KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate histone H3K23 and exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of KAT6A to achieve therapeutic benefit has been a challenge. Here we describe identification of a highly potent, selective, and orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from a benzisoxazole series, which demonstrates anti-tumor activity in correlation with H3K23Ac inhibition in KAT6A over-expressing breast cancer. Transcriptional and epigenetic profiling studies show reduced RNA Pol II binding and downregulation of genes involved in estrogen signaling, cell cycle, Myc and stem cell pathways associated with CTx-648 anti-tumor activity in ER-positive (ER+) breast cancer. CTx-648 treatment leads to potent tumor growth inhibition in ER+ breast cancer in vivo models, including models refractory to endocrine therapy, highlighting the potential for targeting KAT6A in ER+ breast cancer.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Histonas/metabolismo , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Transducción de Señal , Línea Celular Tumoral
17.
Cancers (Basel) ; 14(10)2022 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-35626009

RESUMEN

The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer samples to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.

19.
Cancer Immunol Res ; 9(10): 1125-1140, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34413087

RESUMEN

Immunotherapy success in colorectal cancer is mainly limited to patients whose tumors exhibit high microsatellite instability (MSI). However, there is variability in treatment outcomes within this group, which is in part driven by the frequency and characteristics of tumor-infiltrating immune cells. Indeed, the presence of specific infiltrating immune-cell subsets has been shown to correlate with immunotherapy response and is in many cases prognostic of treatment outcome. Tumor-infiltrating lymphocytes (TIL) can undergo distinct differentiation programs, acquiring features of tissue-residency or exhaustion, a process during which T cells upregulate inhibitory receptors, such as PD-1, and lose functionality. Although residency and exhaustion programs of CD8+ T cells are relatively well studied, these programs have only recently been appreciated in CD4+ T cells and remain largely unknown in tumor-infiltrating natural killer (NK) cells. In this study, we used single-cell RNA sequencing (RNA-seq) data to identify signatures of residency and exhaustion in colorectal cancer-infiltrating lymphocytes, including CD8+, CD4+, and NK cells. We then tested these signatures in independent single-cell data from tumor and normal tissue-infiltrating immune cells. Furthermore, we used versions of these signatures designed for bulk RNA-seq data to explore tumor-intrinsic mutations associated with residency and exhaustion from TCGA data. Finally, using two independent transcriptomic datasets from patients with colon adenocarcinoma, we showed that combinations of these signatures, in particular combinations of NK-cell activity signatures, together with tumor-associated signatures, such as TGFß signaling, were associated with distinct survival outcomes in patients with colon adenocarcinoma.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Inestabilidad de Microsatélites , Linfocitos T CD8-positivos/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Humanos , Inmunoterapia/métodos , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Tasa de Supervivencia , Transcriptoma
20.
Nat Commun ; 12(1): 1920, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772001

RESUMEN

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Antineoplásicos/farmacología , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular/genética , Everolimus/farmacología , Femenino , Proteínas Activadoras de GTPasa/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Imidazoles/farmacología , Proteínas del Tejido Nervioso/metabolismo , Oncogenes/genética , Unión Proteica , Quinolinas/farmacología , Receptores de Estrógenos/metabolismo , Transducción de Señal/efectos de los fármacos
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