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1.
Mol Cell ; 59(1): 75-88, 2015 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-26051178

RESUMEN

Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.


Asunto(s)
Resistencia a Antineoplásicos/genética , Factor de Transcripción E2F1/genética , Histonas/genética , Melanoma/genética , Proteínas Serina-Treonina Quinasas/genética , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular/genética , Factor de Transcripción E2F1/metabolismo , Células HeLa , Histonas/biosíntesis , Humanos , Melanocitos/citología , Melanoma/patología , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Puntos de Control de la Fase S del Ciclo Celular/genética , Análisis de Secuencia de ARN , Factores de Transcripción , Activación Transcripcional
2.
Gastroenterology ; 159(5): 1866-1881.e8, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32717220

RESUMEN

BACKGROUND & AIMS: Development of pancreatic ductal adenocarcinoma (PDA) involves acinar to ductal metaplasia and genesis of tuft cells. It has been a challenge to study these rare cells because of the lack of animal models. We investigated the role of tuft cells in pancreatic tumorigenesis. METHODS: We performed studies with LSL-KrasG12D/+;Ptf1aCre/+ mice (KC; develop pancreatic tumors), KC mice crossed with mice with pancreatic disruption of Pou2f3 (KPouC mice; do not develop tuft cells), or mice with pancreatic disruption of the hematopoietic prostaglandin D synthase gene (Hpgds, KHC mice) and wild-type mice. Mice were allowed to age or were given caerulein to induce pancreatitis; pancreata were collected and analyzed by histology, immunohistochemistry, RNA sequencing, ultrastructural microscopy, and metabolic profiling. We performed laser-capture dissection and RNA-sequencing analysis of pancreatic tissues from 26 patients with pancreatic intraepithelial neoplasia (PanIN), 19 patients with intraductal papillary mucinous neoplasms (IPMNs), and 197 patients with PDA. RESULTS: Pancreata from KC mice had increased formation of tuft cells and higher levels of prostaglandin D2 than wild-type mice. Pancreas-specific deletion of POU2F3 in KC mice (KPouC mice) resulted in a loss of tuft cells and accelerated tumorigenesis. KPouC mice had increased fibrosis and activation of immune cells after administration of caerulein. Pancreata from KPouC and KHC mice had significantly lower levels of prostaglandin D2, compared with KC mice, and significantly increased numbers of PanINs and PDAs. KPouC and KHC mice had increased pancreatic injury after administration of caerulein, significantly less normal tissue, more extracellular matrix deposition, and higher PanIN grade than KC mice. Human PanIN and intraductal papillary mucinous neoplasm had gene expression signatures associated with tuft cells and increased expression of Hpgds messenger RNA compared with PDA. CONCLUSIONS: In mice with KRAS-induced pancreatic tumorigenesis, loss of tuft cells accelerates tumorigenesis and increases the severity of caerulein-induced pancreatic injury, via decreased production of prostaglandin D2. These data are consistent with the hypothesis that tuft cells are a metaplasia-induced tumor attenuating cell type.


Asunto(s)
Carcinoma Ductal Pancreático/prevención & control , Transformación Celular Neoplásica/metabolismo , Páncreas/metabolismo , Neoplasias Pancreáticas/prevención & control , Prostaglandina D2/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Ceruletida , Modelos Animales de Enfermedad , Metabolismo Energético , Fibrosis , Humanos , Interleucinas/genética , Interleucinas/metabolismo , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Ratones Transgénicos , Mutación , Factores de Transcripción de Octámeros/genética , Factores de Transcripción de Octámeros/metabolismo , Páncreas/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pancreatitis/inducido químicamente , Pancreatitis/genética , Pancreatitis/metabolismo , Pancreatitis/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
Cell Mol Life Sci ; 71(3): 379-404, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23652611

RESUMEN

Histone variants are key players in shaping chromatin structure, and, thus, in regulating fundamental cellular processes such as chromosome segregation and gene expression. Emerging evidence points towards a role for histone variants in contributing to tumor progression, and, recently, the first cancer-associated mutation in a histone variant-encoding gene was reported. In addition, genetic alterations of the histone chaperones that specifically regulate chromatin incorporation of histone variants are rapidly being uncovered in numerous cancers. Collectively, these findings implicate histone variants as potential drivers of cancer initiation and/or progression, and, therefore, targeting histone deposition or the chromatin remodeling machinery may be of therapeutic value. Here, we review the mammalian histone variants of the H2A and H3 families in their respective cellular functions, and their involvement in tumor biology.


Asunto(s)
Cromatina/fisiología , Variación Genética , Chaperonas de Histonas/genética , Histonas/genética , Histonas/metabolismo , Modelos Moleculares , Neoplasias/genética , Autoantígenos/genética , Autoantígenos/metabolismo , Proteína A Centromérica , Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Componentes del Gen , Chaperonas de Histonas/metabolismo , Histonas/química , Humanos , Neoplasias/fisiopatología
4.
J Neurosci ; 32(45): 15934-45, 2012 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-23136431

RESUMEN

Choroid plexus epithelial cells (CPECs) have essential developmental and homeostatic roles related to the CSF and blood-CSF barrier they produce. Accordingly, CPEC dysfunction has been implicated in many neurological disorders, such as Alzheimer's disease, and transplant studies have provided proof-of-concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture. During development, CPECs differentiate from preneurogenic neuroepithelial cells and require bone morphogenetic protein (BMP) signaling, but whether BMPs suffice for CPEC induction is unknown. Here we provide evidence for BMP4 sufficiency to induce CPEC fate from neural progenitors derived from mouse embryonic stem cells (ESCs). CPEC specification by BMP4 was restricted to an early time period after neural induction in culture, with peak CPEC competency correlating to neuroepithelial cells rather than radial glia. In addition to molecular, cellular, and ultrastructural criteria, derived CPECs (dCPECs) had functions that were indistinguishable from primary CPECs, including self-assembly into secretory vesicles and integration into endogenous choroid plexus epithelium following intraventricular injection. We then used BMP4 to generate dCPECs from human ESC-derived neuroepithelial cells. These findings demonstrate BMP4 sufficiency to instruct CPEC fate, expand the repertoire of stem cell-derived neural derivatives in culture, and herald dCPEC-based therapeutic applications aimed at the unique interface between blood, CSF, and brain governed by CPECs.


Asunto(s)
Proteína Morfogenética Ósea 4/farmacología , Diferenciación Celular/efectos de los fármacos , Plexo Coroideo/citología , Células Madre Embrionarias/citología , Células Epiteliales/citología , Células-Madre Neurales/citología , Animales , Línea Celular , Células Cultivadas , Plexo Coroideo/efectos de los fármacos , Células Madre Embrionarias/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Humanos , Ratones , Células-Madre Neurales/efectos de los fármacos
5.
Commun Biol ; 6(1): 215, 2023 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-36823213

RESUMEN

Considerable efforts have been made to characterize active enhancer elements, which can be annotated by accessible chromatin and H3 lysine 27 acetylation (H3K27ac). However, apart from poised enhancers that are observed in early stages of development and putative silencers, the functional significance of cis-regulatory elements lacking H3K27ac is poorly understood. Here we show that macroH2A histone variants mark a subset of enhancers in normal and cancer cells, which we coined 'macro-Bound Enhancers', that modulate enhancer activity. We find macroH2A variants localized at enhancer elements that are devoid of H3K27ac in a cell type-specific manner, indicating a role for macroH2A at inactive enhancers to maintain cell identity. In following, reactivation of macro-bound enhancers is associated with oncogenic programs in breast cancer and their repressive role is correlated with the activity of macroH2A2 as a negative regulator of BRD4 chromatin occupancy. Finally, through single cell epigenomic profiling of normal mammary stem cells derived from mice, we show that macroH2A deficiency facilitates increased activity of transcription factors associated with stem cell activity.


Asunto(s)
Proteínas Nucleares , Factores de Transcripción , Ratones , Animales , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Reprogramación Celular/genética , Elementos de Facilitación Genéticos , Cromatina/genética
6.
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
7.
Mol Oncol ; 16(6): 1309-1328, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34669238

RESUMEN

Small-cell lung cancer (SCLC) is a heterogeneous disease, consisting of intratumoral and intertumoral neuroendocrine (ASCL1 and/or NEUROD1), mesenchymal-like, and YAP-driven transcriptional states. Lysine-specific demethylase 1 (LSD1; also known as KDM1A) inhibitors have recently been progressed to clinical trials in SCLC based on a promising preclinical antitumor activity. A potential clinical limitation of LSD1 inhibitors is the heterogeneous drug responses that have been observed in SCLC cell lines and patient-derived models. Based on these observations, we studied molecular and transcriptional signatures that predict patient response to this class of drug. Employing SCLC patient-derived transcriptional signatures, we define that SCLC cell lines sensitive to LSD1 inhibitors are enriched in neuroendocrine transcriptional markers, whereas cell lines enriched in a mesenchymal-like transcriptional program demonstrate intrinsic resistance to LSD1 inhibitors. We have identified a reversible, adaptive resistance mechanism to LSD1 inhibitors through epigenetic reprogramming to a TEAD4-driven mesenchymal-like state. Our data suggest that only a segment of SCLC patients, with a defined neuroendocrine differentiation state, will likely benefit from LSD1 inhibitors. It provides novel evidence for the selection of a TEAD4-driven mesenchymal-like subpopulation resistant to LSD1 inhibitors in SCLC patients that may require effective drug combinations to sustain effective clinical responses.


Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Proteínas de Unión al ADN/genética , Resistencia a Medicamentos , Histona Demetilasas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Musculares , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Factores de Transcripción de Dominio TEA , Factores de Transcripción/genética
8.
Sci Rep ; 12(1): 12501, 2022 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-35864202

RESUMEN

The synthetic lethal association between BRCA deficiency and poly (ADP-ribose) polymerase (PARP) inhibition supports PARP inhibitor (PARPi) clinical efficacy in BRCA-mutated tumors. PARPis also demonstrate activity in non-BRCA mutated tumors presumably through induction of PARP1-DNA trapping. Despite pronounced clinical response, therapeutic resistance to PARPis inevitably develops. An abundance of knowledge has been built around resistance mechanisms in BRCA-mutated tumors, however, parallel understanding in non-BRCA mutated settings remains insufficient. In this study, we find a strong correlation between the epithelial-mesenchymal transition (EMT) signature and resistance to a clinical PARPi, Talazoparib, in non-BRCA mutated tumor cells. Genetic profiling demonstrates that SNAI2, a master EMT transcription factor, is transcriptionally induced by Talazoparib treatment or PARP1 depletion and this induction is partially responsible for the emerging resistance. Mechanistically, we find that the PARP1 protein directly binds to SNAI2 gene promoter and suppresses its transcription. Talazoparib treatment or PARP1 depletion lifts PARP1-mediated suppression and increases chromatin accessibility around SNAI2 promoters, thus driving SNAI2 transcription and drug resistance. We also find that depletion of the chromatin remodeler CHD1L suppresses SNAI2 expression and reverts acquired resistance to Talazoparib. The PARP1/CHD1L/SNAI2 transcription axis might be therapeutically targeted to re-sensitize Talazoparib in non-BRCA mutated tumors.


Asunto(s)
Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Cromatina , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Humanos , Neoplasias/genética , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/genética , Factores de Transcripción de la Familia Snail/genética
9.
Mol Cancer Ther ; 21(1): 3-15, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34737197

RESUMEN

Protein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with in vitro and in vivo characterization of clinical candidate PF-06939999. Acquired resistance mechanisms were explored through the development of drug resistant cell lines. Our data highlight compound-specific resistance mutations in the PRMT5 enzyme that demonstrate structural constraints in the cofactor binding site that prevent emergence of complete resistance to SAM site inhibitors. PRMT5 inhibition by PF-06939999 treatment reduced proliferation of non-small cell lung cancer (NSCLC) cells, with dose-dependent decreases in symmetric dimethyl arginine (SDMA) levels and changes in alternative splicing of numerous pre-mRNAs. Drug sensitivity to PF-06939999 in NSCLC cells associates with cancer pathways including MYC, cell cycle and spliceosome, and with mutations in splicing factors such as RBM10. Translation of efficacy in mouse tumor xenograft models with splicing mutations provides rationale for therapeutic use of PF-06939999 in the treatment of splicing dysregulated NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , S-Adenosilmetionina/metabolismo , Animales , Apoptosis , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Proliferación Celular , Resistencia a Medicamentos , Femenino , Humanos , Neoplasias Pulmonares/patología , Ratones
10.
Front Physiol ; 11: 88, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32116793

RESUMEN

Chronic pancreatitis, a known risk factor for the development of pancreatic ductal adenocarcinoma (PDA), is a serious, widespread medical condition characterized by inflammation, fibrosis, and acinar to ductal metaplasia (ADM). ADM is a cell type transdifferentiation event where pancreatic acinar cells become ductal-like under conditions of injury or oncogenic mutation. Here, we show that chronic pancreatitis and ADM in genetically wild type mice results in the formation of a significant population of chemosensory tuft cells. Transcriptomic analyses of pancreatitis tuft cells identify expression of inflammatory mediators, consistent with a role for tuft cells in injury progression and/or resolution. Though similar to tuft cell populations in other organs and disease systems, we identified a number of key differences that suggest context-specific tuft cell functions. We evaluated seven different mouse strains for tuft cell formation in response to chronic injury and identified significant heterogeneity reflecting varying proclivity for epithelial plasticity between strains. These results have interesting implications in the role of epithelial plasticity and heterogeneity in pancreatitis and highlight the importance of mouse strain selection when modeling human disease.

11.
Cell Rep ; 31(10): 107742, 2020 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-32521267

RESUMEN

Lineage plasticity is important for the development of basal-like breast cancer (BLBC), an aggressive cancer subtype. While BLBC is likely to originate from luminal progenitor cells, it acquires substantial basal cell features and contains a heterogenous collection of cells exhibiting basal, luminal, and hybrid phenotypes. Why luminal progenitors are prone to BLBC transformation and what drives luminal-to-basal reprogramming remain unclear. Here, we show that the transcription factor SOX9 acts as a determinant for estrogen-receptor-negative (ER-) luminal stem/progenitor cells (LSPCs). SOX9 controls LSPC activity in part by activating both canonical and non-canonical nuclear factor κB (NF-κB) signaling. Inactivation of TP53 and RB via expression of SV40 TAg in a BLBC mouse tumor model leads to upregulation of SOX9, which drives luminal-to-basal reprogramming in vivo. Furthermore, SOX9 deletion inhibits the progression of ductal carcinoma in situ (DCIS)-like lesions to invasive carcinoma. These data show that ER- LSPC determinant SOX9 acts as a lineage plasticity driver for BLBC progression.


Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Factor de Transcripción SOX9/metabolismo , Animales , Linaje de la Célula , Plasticidad de la Célula/fisiología , Proliferación Celular/fisiología , Progresión de la Enfermedad , Femenino , Humanos , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regulación hacia Arriba
12.
Cell Rep ; 29(2): 495-510.e6, 2019 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-31597106

RESUMEN

Technological improvements enable single-cell epigenetic analyses of organ development. We reasoned that high-resolution single-cell chromatin accessibility mapping would provide needed insight into the epigenetic reprogramming and transcriptional regulators involved in normal mammary gland development. Here, we provide a single-cell resource of chromatin accessibility for murine mammary development from the peak of fetal mammary stem cell (fMaSC) functional activity in late embryogenesis to the differentiation of adult basal and luminal cells. We find that the chromatin landscape within individual cells predicts both gene accessibility and transcription factor activity. The ability of single-cell chromatin profiling to separate E18 fetal mammary cells into clusters exhibiting basal-like and luminal-like chromatin features is noteworthy. Such distinctions were not evident in analyses of droplet-based single-cell transcriptomic data. We present a web application as a scientific resource for facilitating future analyses of the gene regulatory networks involved in mammary development.


Asunto(s)
Linaje de la Célula/genética , Cromatina/metabolismo , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/crecimiento & desarrollo , Análisis de la Célula Individual , Transcripción Genética , Animales , Diferenciación Celular/genética , Epigénesis Genética , Femenino , Feto/citología , Regulación del Desarrollo de la Expresión Génica , Genoma , Ratones , Factores de Transcripción/metabolismo
13.
Cancer Cell ; 34(3): 466-482.e6, 2018 09 10.
Artículo en Inglés | MEDLINE | ID: mdl-30174241

RESUMEN

Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.


Asunto(s)
Neoplasias de la Mama/genética , Plasticidad de la Célula/genética , Neoplasias Mamarias Experimentales/genética , Factores de Transcripción SOXE/metabolismo , Adulto , Animales , Neoplasias de la Mama/patología , Diferenciación Celular/genética , Línea Celular Tumoral/trasplante , Transformación Celular Neoplásica/genética , Embrión de Mamíferos , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/patología , Glándulas Mamarias Humanas/crecimiento & desarrollo , Glándulas Mamarias Humanas/patología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Transgénicos , Cresta Neural/crecimiento & desarrollo , Cresta Neural/patología , Factores de Transcripción SOXE/genética , Células Madre/patología
14.
Cell Rep ; 24(6): 1653-1666.e7, 2018 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-30089273

RESUMEN

The mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge of developmental kinetics and mechanisms of lineage specification is lacking. We address this significant knowledge gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, and adult mouse mammary development. From these data, we map the chronology of transcriptionally and epigenetically distinct cell states and distinguish fetal mammary stem cells (fMaSCs) from their precursors and progeny. fMaSCs show balanced co-expression of factors associated with discrete adult lineages and a metabolic gene signature that subsides during maturation but reemerges in some human breast cancers and metastases. These data provide a useful resource for illuminating mammary cell heterogeneity, the kinetics of differentiation, and developmental correlates of tumorigenesis.


Asunto(s)
Glándulas Mamarias Animales/crecimiento & desarrollo , Animales , Diferenciación Celular/fisiología , Femenino , Humanos , Glándulas Mamarias Animales/citología , Ratones , Células Madre/metabolismo , Transcriptoma
15.
Oncotarget ; 8(51): 88421-88436, 2017 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-29179446

RESUMEN

Cancer cell invasion is an obligatory step for metastatic dissemination that contributes to rapid relapse and a poorer survival in triple negative breast cancer (TNBC) patients. Development of novel therapeutic strategies to block tumor invasion is an unmet need in the treatment of cancer. We reported that the selective inhibition of the PAH2 domain of SIN3A protein function markedly suppressed metastatic dissemination to the lungs in TNBC xenograft bearing mice. Here, we show that TNBC cell lines treated with Sin3 interaction domain (SID) decoy peptides that bind to PAH2 display a strong in vitro inhibition of transwell invasion. This is accompanied by actin cytoskeleton reorganization with increased cortical actin deposition and downregulation of known Wnt target genes that are associated with epithelial to mesenchymal transition (EMT) and cancer cell invasion. Wnt pathway inhibition by SID decoy peptide was confirmed by decreased Wnt reporter activity and altered cytoplasmic localization of nuclear ß-catenin. TGIF1, a transcription factor that modulates Wnt signaling and known to interact with the PAH2 domain of SIN3A, can be dissociated from the SIN3A complex by SID decoys. TGIF1 knockdown inhibits WNT target genes and in vitro cell invasion suggesting that TGIF1 might be a key target of the SID decoys to block tumor invasion. Taken together, targeting SIN3 function using SID decoys is a novel strategy to reverse invasion and the EMT program in TNBC translating into the inhibition of metastasis dissemination and eradication of residual disease.

16.
Cell Rep ; 16(2): 472-486, 2016 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-27346354

RESUMEN

Chromatin-mediated processes influence the development and progression of breast cancer. Using murine mammary carcinoma-derived tumorspheres as a functional readout for an aggressive breast cancer phenotype, we performed a loss-of-function screen targeting 60 epigenetic regulators. We identified the Polycomb protein Cbx8 as a key regulator of mammary carcinoma both in vitro and in vivo. Accordingly, Cbx8 is overexpressed in human breast cancer and correlates with poor survival. Our genomic analyses revealed that Cbx8 positively regulates Notch signaling by maintaining H3K4me3 levels on Notch-network gene promoters. Ectopic expression of Notch1 partially rescues tumorsphere formation in Cbx8-depleted cells. We find that Cbx8 associates with non-PRC1 complexes containing the H3K4 methyltransferase complex component WDR5, which together regulate Notch gene expression. Thus, our study implicates a key non-canonical role for Cbx8 in promoting breast tumorigenesis.


Asunto(s)
Neoplasias Mamarias Animales/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Proteínas del Grupo Polycomb/fisiología , Proteínas/fisiología , Animales , Carcinogénesis/metabolismo , Línea Celular Tumoral , Epigénesis Genética , Células Epiteliales/metabolismo , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Sitios Genéticos , Histonas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Ratones Transgénicos , Células Madre Neoplásicas/metabolismo , Complejo Represivo Polycomb 1 , Procesamiento Proteico-Postraduccional , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Esferoides Celulares/metabolismo , Carga Tumoral
17.
Oncotarget ; 6(33): 34087-105, 2015 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-26460951

RESUMEN

Triple negative breast cancer (TNBC) is characterized by a poorly differentiated phenotype and limited treatment options. Aberrant epigenetics in this subtype represent a potential therapeutic opportunity, but a better understanding of the mechanisms contributing to the TNBC pathogenesis is required. The SIN3 molecular scaffold performs a critical role in multiple cellular processes, including epigenetic regulation, and has been identified as a potential therapeutic target. Using a competitive peptide corresponding to the SIN3 interaction domain of MAD (Tat-SID), we investigated the functional consequences of selectively blocking the paired amphipathic α-helix (PAH2) domain of SIN3. Here, we report the identification of the SID-containing adaptor PF1 as a factor required for maintenance of the TNBC stem cell phenotype and epithelial-to-mesenchymal transition (EMT). Tat-SID peptide blocked the interaction between SIN3A and PF1, leading to epigenetic modulation and transcriptional downregulation of TNBC stem cell and EMT markers. Importantly, Tat-SID treatment also led to a reduction in primary tumor growth and disseminated metastatic disease in vivo. In support of these findings, knockdown of PF1 expression phenocopied treatment with Tat-SID both in vitro and in vivo. These results demonstrate a critical role for a complex containing SIN3A and PF1 in TNBC and provide a rational for its therapeutic targeting.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Proteínas de Homeodominio/metabolismo , Células Madre Neoplásicas/patología , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Femenino , Proteínas de Homeodominio/genética , Humanos , Ratones , Estructura Terciaria de Proteína , Complejo Correpresor Histona Desacetilasa y Sin3 , Esferoides Celulares , Factores de Transcripción/genética , Células Tumorales Cultivadas
18.
Nat Commun ; 6: 6170, 2015 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-25636082

RESUMEN

Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7-18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARß and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.


Asunto(s)
Factor de Transcripción COUP I/metabolismo , Receptores de Ácido Retinoico/metabolismo , Factor de Transcripción SOX9/metabolismo , Animales , Línea Celular Tumoral , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Neoplasias de la Próstata/metabolismo , Interferencia de ARN , Células Tumorales Cultivadas
19.
Dev Cell ; 23(5): 981-94, 2012 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-23153495

RESUMEN

How dermal papilla (DP) niche cells regulate hair follicle progenitors to control hair growth remains unclear. Using Tbx18(Cre) to target embryonic DP precursors, we ablate the transcription factor Sox2 early and efficiently, resulting in diminished hair shaft outgrowth. We find that DP niche expression of Sox2 controls the migration speed of differentiating hair shaft progenitors. Transcriptional profiling of Sox2 null DPs reveals increased Bmp6 and decreased BMP inhibitor Sostdc1, a direct Sox2 transcriptional target. Subsequently, we identify upregulated BMP signaling in knockout hair shaft progenitors and demonstrate that Bmp6 inhibits cell migration, an effect that can be attenuated by Sostdc1. A shorter and Sox2-negative hair type lacks Sostdc1 in the DP and shows reduced migration and increased BMP activity of hair shaft progenitors. Collectively, our data identify Sox2 as a key regulator of hair growth that controls progenitor migration by fine-tuning BMP-mediated mesenchymal-epithelial crosstalk.


Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Folículo Piloso/embriología , Folículo Piloso/metabolismo , Cabello/crecimiento & desarrollo , Factores de Transcripción SOXB1/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteína Morfogenética Ósea 6/metabolismo , Proteínas Morfogenéticas Óseas/deficiencia , Movimiento Celular , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Folículo Piloso/citología , Folículo Piloso/crecimiento & desarrollo , Ratones , Ratones Noqueados , Ratones Transgénicos , Factores de Transcripción SOXB1/deficiencia , Factores de Transcripción SOXB1/genética , Transducción de Señal , Transcriptoma
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