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1.
Nature ; 604(7905): 354-361, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35355015

RESUMEN

Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the palms of the hands, soles of the feet or under the nails3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma and enrichment for CRKL amplifications in acral melanoma. We modelled these changes in transgenic zebrafish models and found that CRKL-driven tumours formed predominantly in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin and limb melanocytes, when compared with body melanocytes, revealed a positional identity gene programme typified by posterior HOX13 genes. This positional gene programme synergized with CRKL to amplify insulin-like growth factor (IGF) signalling and drive tumours at acral sites. Abrogation of this CRKL-driven programme eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Animales , Animales Modificados Genéticamente , Carcinogénesis/genética , Pie , Mano , Humanos , Melanoma/patología , Uñas , Oncogenes/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Transcripción Genética , Pez Cebra/genética , Melanoma Cutáneo Maligno
2.
Nature ; 527(7578): 329-35, 2015 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-26524530

RESUMEN

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6ß4 and α6ß1 were associated with lung metastasis, while exosomal integrin αvß5 was linked to liver metastasis. Targeting the integrins α6ß4 and αvß5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.


Asunto(s)
Encéfalo/metabolismo , Exosomas/metabolismo , Integrinas/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Tropismo , Animales , Biomarcadores/metabolismo , Encéfalo/citología , Línea Celular Tumoral , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Genes src , Humanos , Integrina alfa6beta1/metabolismo , Integrina alfa6beta4/antagonistas & inhibidores , Integrina alfa6beta4/metabolismo , Cadenas beta de Integrinas/metabolismo , Integrina beta4/metabolismo , Integrinas/antagonistas & inhibidores , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/citología , Pulmón/citología , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Fosforilación , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/metabolismo , Proteínas S100/genética
3.
bioRxiv ; 2024 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-39229155

RESUMEN

Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an Epithelial-Mesenchymal Transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment (TME) may limit melanoma invasion through altered cell-cell interactions.

4.
Elife ; 112022 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-36538362

RESUMEN

Cancer cells exist in a complex ecosystem with numerous other cell types in the tumor microenvironment (TME). The composition of this tumor/TME ecosystem will vary at each anatomic site and affects phenotypes such as initiation, metastasis, and drug resistance. A mechanistic understanding of the large number of cell-cell interactions between tumor and TME requires models that allow us to both characterize as well as genetically perturb this complexity. Zebrafish are a model system optimized for this problem, because of the large number of existing cell-type-specific drivers that can label nearly any cell in the TME. These include stromal cells, immune cells, and tissue resident normal cells. These cell-type-specific promoters/enhancers can be used to drive fluorophores to facilitate imaging and also CRISPR cassettes to facilitate perturbations. A major advantage of the zebrafish is the ease by which large numbers of TME cell types can be studied at once, within the same animal. While these features make the zebrafish well suited to investigate the TME, the model has important limitations, which we also discuss. In this review, we describe the existing toolset for studying the TME using zebrafish models of cancer and highlight unique biological insights that can be gained by leveraging this powerful resource.


Asunto(s)
Neoplasias , Pez Cebra , Animales , Microambiente Tumoral , Ecosistema , Neoplasias/genética , Neoplasias/patología , Modelos Biológicos
5.
Nat Commun ; 12(1): 6278, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34725363

RESUMEN

During tumor progression, cancer cells come into contact with various non-tumor cell types, but it is unclear how tumors adapt to these new environments. Here, we integrate spatially resolved transcriptomics, single-cell RNA-seq, and single-nucleus RNA-seq to characterize tumor-microenvironment interactions at the tumor boundary. Using a zebrafish model of melanoma, we identify a distinct "interface" cell state where the tumor contacts neighboring tissues. This interface is composed of specialized tumor and microenvironment cells that upregulate a common set of cilia genes, and cilia proteins are enriched only where the tumor contacts the microenvironment. Cilia gene expression is regulated by ETS-family transcription factors, which normally act to suppress cilia genes outside of the interface. A cilia-enriched interface is conserved in human patient samples, suggesting it is a conserved feature of human melanoma. Our results demonstrate the power of spatially resolved transcriptomics in uncovering mechanisms that allow tumors to adapt to new environments.


Asunto(s)
Neoplasias/genética , Transcriptoma , Microambiente Tumoral , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/metabolismo , RNA-Seq , Pez Cebra/genética , Pez Cebra/metabolismo
6.
Elife ; 102021 06 11.
Artículo en Inglés | MEDLINE | ID: mdl-34114952

RESUMEN

Lipid droplets are lipid storage organelles found in nearly all cell types from adipocytes to cancer cells. Although increasingly implicated in disease, current methods to study lipid droplets in vertebrate models rely on static imaging or the use of fluorescent dyes, limiting investigation of their rapid in vivo dynamics. To address this, we created a lipid droplet transgenic reporter in whole animals and cell culture by fusing tdTOMATO to Perilipin-2 (PLIN2), a lipid droplet structural protein. Expression of this transgene in transparent casper zebrafish enabled in vivo imaging of adipose depots responsive to nutrient deprivation and high-fat diet. Simultaneously, we performed a large-scale in vitro chemical screen of 1280 compounds and identified several novel regulators of lipolysis in adipocytes. Using our Tg(-3.5ubb:plin2-tdTomato) zebrafish line, we validated several of these novel regulators and revealed an unexpected role for nitric oxide in modulating adipocyte lipid droplets. Similarly, we expressed the PLIN2-tdTOMATO transgene in melanoma cells and found that the nitric oxide pathway also regulated lipid droplets in cancer. This model offers a tractable imaging platform to study lipid droplets across cell types and disease contexts using chemical, dietary, or genetic perturbations.


Organisms need fat molecules as a source of energy and as building blocks, but these 'lipids' can also damage cells if they are present in large amounts. Cells guard against such toxicity by safely sequestering lipids in specialized droplets that participate in a range of biological processes. For instance, these structures can quickly change size to store or release lipids depending on the energy demands of a cell. It is possible to image lipid droplets ­ using, for example, dyes that preferentially stain fat ­ but often these methods can only yield a snapshot: tracking lipid droplet dynamics over time remains difficult. Lumaquin, Johns et al. therefore set out to develop a new method that could label lipid droplets and monitor their behaviour 'live' in the cells of small, transparent zebrafish larvae. First, the fish were genetically manipulated so that a key protein found in lipid droplets would carry a fluorescent tag: this made the structures strongly fluorescent and easy to track over time. And indeed, Lumaquin, Johns et al. could monitor changes in the droplets depending on the fish diet, with the structures getting bigger when the animal received rich food, and shrinking when resources were scarce. Finally, experiments were conducted to screen for compounds that could lead to lipids being released in fat cells. The new imaging technique was then used to confirm the effect of these molecules in live cells, revealing an unexpected role for a signalling molecule known as nitric oxide, which also turned out to be regulating lipid droplets in cancerous cells. Further work then showed that drugs affecting nitric oxide could modulate lipid droplet size in both normal and tumor cells. This work has validated a new method to study the real-time behavior of lipid droplets and their responses to different stimuli in living cells. In the future, Lumaquin, Johns et al. hope that the technique will help to shed new light on how lipids are involved in both healthy and abnormal biological processes.


Asunto(s)
Adipocitos/metabolismo , Gotas Lipídicas/metabolismo , Proteínas Luminiscentes/metabolismo , Perilipina-2/metabolismo , Proteínas de Pez Cebra/metabolismo , Tejido Adiposo/metabolismo , Animales , Línea Celular Tumoral , Dieta Alta en Grasa , Metabolismo de los Lípidos , Lipólisis , Melanoma/metabolismo , Óxido Nítrico/metabolismo , Compuestos de Fenilurea/farmacología , Pez Cebra/metabolismo
7.
Science ; 373(6559): eabc1048, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34516843

RESUMEN

Oncogenes only transform cells under certain cellular contexts, a phenomenon called oncogenic competence. Using a combination of a human pluripotent stem cell­derived cancer model along with zebrafish transgenesis, we demonstrate that the transforming ability of BRAFV600E along with additional mutations depends on the intrinsic transcriptional program present in the cell of origin. In both systems, melanocytes are less responsive to mutations, whereas both neural crest and melanoblast populations are readily transformed. Profiling reveals that progenitors have higher expression of chromatin-modifying enzymes such as ATAD2, a melanoma competence factor that forms a complex with SOX10 and allows for expression of downstream oncogenic and neural crest programs. These data suggest that oncogenic competence is mediated by regulation of developmental chromatin factors, which then allow for proper response to those oncogenes.


Asunto(s)
Carcinogénesis/genética , Carcinogénesis/patología , Cromatina/metabolismo , Melanoma/genética , Melanoma/patología , Cresta Neural/patología , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Animales , Animales Modificados Genéticamente , Cromatina/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Melanocitos/metabolismo , Melanocitos/patología , Ratones , Neoplasias Experimentales , Células Madre Neoplásicas/patología , Cresta Neural/metabolismo , Células Madre Pluripotentes/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Transcripción Genética , Pez Cebra
8.
Int J Offender Ther Comp Criminol ; 52(1): 112-26, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17615437

RESUMEN

Human verbal language communicates both manifest and latent messages concerning the speaker's world and behavior. To understand his world and analyze his problems,(1) it is important to decode the latent messages as they may hint at the root causes. The authors present a discourse analysis of a prisoner's text and a semantic and morphological analysis of it. This text reflects contempt for the law and its representatives, together with a weak attachment to legitimate society, neutralization of personal responsibility, denial of guilt, and low self-esteem. Sociolinguistic and psycholinguistic analysis points toward a more profound evaluation of the perceptions and world of the speaker. It seems that he yearns for attachment, for understanding and social acceptance, and perhaps even to abandon crime. The prisoner's latent feelings of helplessness and fear of humiliation may help the therapist establish a therapeutic relationship and help him change his perceptions and behavior.


Asunto(s)
Trastornos Mentales/diagnóstico , Determinación de la Personalidad , Prisioneros/psicología , Psicolingüística , Socialización , Conducta Verbal , Adulto , Negación en Psicología , Culpa , Humanos , Entrevista Psicológica , Masculino , Trastornos Mentales/psicología , Apego a Objetos , Teoría de Construcción Personal , Racionalización , Autoimagen , Responsabilidad Social , Vocabulario
9.
Isr J Psychiatry Relat Sci ; 52(2): 121-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26431417

RESUMEN

BACKGROUND: Assessment of risk of violent behavior in forensic psychiatric practice is a complex and responsible clinical task and the use of a valid instrument can make the expert's work more effective. The Historical Clinical and Risk Management scale 20 (HCR-20) is a widely accepted measure of the risk of violence, sexual and criminal behavior. The aim of this study was to validate the HCR-20 in Israeli psychiatric inpatient settings. METHOD: In a prospective design, data were collected on 150 male patients aged 15-65, diagnosed with ICD-10 schizophrenia, who were hospitalized in three wards: an acute psychiatric ward (n=50), a high security ward (n=50), and an open ward (n=50). The HCR-20, as the predictor measure, and the Positive and Negative Syndrome Scale, as a concurrent measure, werecompleted at baseline, and the Violence Assessment Scale, as the outcome measure, was completed at 6-, 12- and 18-month follow-up points. RESULTS: Internal consistency reliability was good for the total HCR-20 scale, satisfactory for the H-subscale, but low for the C- and R-subscales. Concurrent validity was good for the C-subscale, and discriminative validity was reasonable for the C- and H-subscales. The total scale as well as the Historical and Clinical subscales predicted the risk of physical as well as physical/sexual violent behavior at both 6- and 18-month follow-up points. CONCLUSIONS: Appropriate psychometric properties of the HCR-20 suggest that it can serve as a useful measure of the risk of violent behavior in psychiatric settings in Israel. Further research is necessary to confirm norms and cut-off scores, using a larger representative sample.


Asunto(s)
Escalas de Valoración Psiquiátrica/normas , Esquizofrenia/diagnóstico , Violencia , Adolescente , Adulto , Anciano , Humanos , Masculino , Persona de Mediana Edad , Servicio de Psiquiatría en Hospital , Psicometría , Reproducibilidad de los Resultados , Medición de Riesgo , Esquizofrenia/complicaciones , Adulto Joven
10.
Exp Hematol ; 42(12): 1022-1030.e1, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25193880

RESUMEN

Iron, an essential nutrient for cellular growth and proliferation, enters cells via clathrin-mediated endocytosis. The clathrin assembly lymphoid myeloid (CALM) protein plays an essential role in the cellular import of iron by clathrin-mediated endocytosis. CALM-AF10 leukemias harbor a single copy of the normal CALM gene and therefore may be more sensitive to the growth-inhibitory effect of iron restriction compared with normal hematopoietic cells. We found that CALM heterozygous (CALM(HET)) murine fibroblasts exhibit signs of iron deficiency, with increased surface transferrin receptor levels and reduced growth rates. CALM(HET) hematopoietic cells are more sensitive in vitro to iron chelators than their wild type counterparts. Iron chelation also displayed toxicity toward cultured CALM(HET)CALM-AF10 leukemia cells, and this effect was additive to that of chemotherapy. In mice transplanted with CALM(HET)CALM-AF10 leukemia, we found that dietary iron restriction reduced tumor burden in the spleen. However, dietary iron restriction, used alone or in conjunction with chemotherapy, did not increase survival of mice with CALM(HET)CALM-AF10 leukemia. In summary, although CALM heterozygosity results in iron deficiency and increased sensitivity to iron chelation in vitro, our data in mice do not suggest that iron depletion strategies would be beneficial for the therapy of CALM-AF10 leukemia patients.


Asunto(s)
Hierro de la Dieta/administración & dosificación , Hierro/metabolismo , Leucemia Experimental/terapia , Proteínas de Fusión Oncogénica/metabolismo , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzoatos/farmacología , Benzoatos/uso terapéutico , Transporte Biológico , Línea Celular Tumoral , Terapia por Quelación , Terapia Combinada , Deferasirox , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Fibroblastos/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Heterocigoto , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Hierro de la Dieta/farmacocinética , Leucemia Experimental/metabolismo , Ratones , Ratones Noqueados , Proteínas de Ensamble de Clatrina Monoméricas/deficiencia , Proteínas de Ensamble de Clatrina Monoméricas/genética , Quimera por Radiación , Bazo/patología , Triazoles/farmacología , Triazoles/uso terapéutico , Carga Tumoral
11.
Int J Offender Ther Comp Criminol ; 57(3): 312-31, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22116962

RESUMEN

The current study examines the differences between four groups of offenders (N = 230) according to the type of crime they committed: domestic violence, sex offenses, traffic violations, and nonspecific violence offenses. The study was conducted on the offenders undergoing treatment in the Israeli Adult Probation Service. A comparison between the groups included an examination of the differences in aggression levels, anxiety levels, and two Minnesota Multiphasic Personality Inventory-2 (MMPI-2) scales-the Psychopathic Deviate (PD-4) and the Antisocial Practices (ASP) scales. The findings provide a glimpse of the features that characterize each group, in relation to each other and in relation to the body of literature. The domestic violence group differed from the other groups in most of the research variables. They were found to have low anxiety levels and high aggression levels. Together with other findings that pointed to antisocial practices and attitudes, this group constitutes a population that is violent and aggressive to a far greater extent compared with the other groups. Sex offenders were found to be a unique group that does not fit in the "classic offenders" category. They were found to have low aggression levels and high anxiety levels and their scores on PD-4 and ASP scales were low compared with the other groups. The traffic group was characterized with typically low levels of anxiety and high levels of physical aggression. This group also obtained high scores on ASP scale and the measure that examined confrontation with authority figures. Finally, study findings did not indicate characteristics that typify the nonspecific violence offenses.


Asunto(s)
Trastorno de Personalidad Antisocial/diagnóstico , Trastorno de Personalidad Antisocial/psicología , Crimen/legislación & jurisprudencia , Crimen/psicología , MMPI/estadística & datos numéricos , Prisioneros/legislación & jurisprudencia , Prisioneros/psicología , Socialización , Adulto , Agresión/psicología , Trastornos de Ansiedad/diagnóstico , Trastornos de Ansiedad/psicología , Humanos , Individualidad , Israel , Masculino , Persona de Mediana Edad , Pronóstico , Delitos Sexuales/legislación & jurisprudencia , Delitos Sexuales/psicología , Maltrato Conyugal/legislación & jurisprudencia , Maltrato Conyugal/psicología , Violencia/legislación & jurisprudencia , Violencia/psicología
12.
Nutrients ; 5(8): 2836-59, 2013 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-23887041

RESUMEN

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention in a variety of cancers. Here, we will review iron homeostasis in non-malignant and malignant cells, the widespread effects of iron depletion on the cell, the various iron chelators that have been explored in the treatment of cancer, and the tumor types that have been most commonly studied in the context of iron chelation.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Hierro de la Dieta/uso terapéutico , Neoplasias/tratamiento farmacológico , Anemia Ferropénica/complicaciones , Puntos de Control del Ciclo Celular , División Celular , Proliferación Celular/efectos de los fármacos , Quelantes/química , Quelantes/farmacología , Homeostasis/efectos de los fármacos , Humanos , Neoplasias/complicaciones
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