RESUMEN
The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
Asunto(s)
Anticuerpos Neutralizantes/farmacología , Antígenos CD36/antagonistas & inhibidores , Neoplasias de la Boca/patología , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/prevención & control , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Antígenos CD36/genética , Antígenos CD36/inmunología , Antígenos CD36/metabolismo , Proliferación Celular , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Receptores de Hialuranos/metabolismo , Metabolismo de los Lípidos/genética , Metástasis Linfática/genética , Metástasis Linfática/patología , Masculino , Ratones , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/metabolismo , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/genética , Células Madre Neoplásicas/metabolismo , Ácido Palmítico/administración & dosificación , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacología , Penetrancia , Pronóstico , Transcriptoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Prep1 homeodomain transcription factor has recently been recognized as a tumor suppressor. Among other features, haploinsufficiency of Prep1 is able to strongly accelerate the B-lymphomagenesis in EµMyc mice. Now we report that this occurs concomitantly with a change in the type of B-cell lymphomas generated by the Myc oncogene. Indeed, the tumors generated in the EµMyc-Prep1(+/-) mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EµMyc-Prep1(+/+) mice are more differentiated being invariably IgM(+). Moreover, we show that Prep1 is in fact required for the differentiation of Pro-B and Pre-B cells into IgM(+) lymphocytes and/or their proliferation, thus showing also how a normal function of Prep1 affects EµMyc lymphomagenesis. Finally, we show that the haploinsufficiency of Prep1 is accompanied with a major decrease of Myc-induced apoptosis and that the haploinsufficieny is sufficient for all these effects because the second allele of Prep1 is not lost even at late stages. Therefore, the tumor-suppressive activity of Prep1 is intertwined with both the interference with Myc-induced apoptosis as well as with natural developmental functions of the protein.
Asunto(s)
Linfocitos B/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Linfoma de Células B/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo , Alelos , Animales , Apoptosis , Linfocitos B/citología , Proliferación Celular , Citometría de Flujo/métodos , Haploinsuficiencia , Inmunofenotipificación , Antígenos Comunes de Leucocito/biosíntesis , Pérdida de Heterocigocidad , Linfocitos/citología , Linfoma de Células B/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodosRESUMEN
Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex 1 (PRC1)-associated protein, maintains human epidermal stem cells as slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its antisenescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors such as Ezh2, Dnmt1, and Bmi1 to prevent the active stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation.
Asunto(s)
Células Madre Adultas/metabolismo , Proliferación Celular , Queratinocitos/metabolismo , Proteínas Represoras/metabolismo , Proteína SUMO-1/metabolismo , Adulto , Células Madre Adultas/patología , Diferenciación Celular/genética , Células Cultivadas , Senescencia Celular/genética , Ensamble y Desensamble de Cromatina , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteína Potenciadora del Homólogo Zeste 2 , Epidermis/patología , Prepucio/patología , Perfilación de la Expresión Génica , Humanos , Recién Nacido , Queratinocitos/patología , Ligasas , Masculino , Mutagénesis Sitio-Dirigida , Proteínas Nucleares/metabolismo , Complejo Represivo Polycomb 1 , Complejo Represivo Polycomb 2 , Proteínas del Grupo Polycomb , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/genética , Proteínas Represoras/genética , Factores de Transcripción/metabolismo , Ubiquitina-Proteína LigasasRESUMEN
Jarid2 is required for the genomic recruitment of the polycomb repressive complex-2 (PRC2) in embryonic stem cells. However, its specific role during late development and adult tissues remains largely uncharacterized. Here, we show that deletion of Jarid2 in mouse epidermis reduces the proliferation and potentiates the differentiation of postnatal epidermal progenitors, without affecting epidermal development. In neonatal epidermis, Jarid2 deficiency reduces H3K27 trimethylation, a chromatin repressive mark, in epidermal differentiation genes previously shown to be targets of the PRC2. However, in adult epidermis Jarid2 depletion does not affect interfollicular epidermal differentiation but results in delayed hair follicle (HF) cycling as a consequence of decreased proliferation of HF stem cells and their progeny. We conclude that Jarid2 is required for the scheduled proliferation of epidermal stem and progenitor cells necessary to maintain epidermal homeostasis.
