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1.
Cell Stem Cell ; 27(2): 284-299.e8, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32693087

RESUMEN

SMAD pathways govern epithelial proliferation, and transforming growth factor ß (TGF-ß and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse epithelium, LEFTY1 expression in a subset of luminal cells and rare basal cells opposes BMP7 to promote ductal branching. LEFTY1 binds BMPR2 to suppress BMP7-induced activation of SMAD5, and this LEFTY1-BMPR2 interaction is specific to tumor-initiating cells in triple-negative breast cancer xenografts that rely on LEFTY1 for growth. These results suggest that LEFTY1 is an endogenous dual-SMAD inhibitor and that suppressing its function may represent a therapeutic vulnerability in breast cancer.


Asunto(s)
Transducción de Señal , Factor de Crecimiento Transformador beta , Animales , Carcinogénesis , Transformación Celular Neoplásica , Ratones
2.
Science ; 367(6476): 405-411, 2020 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-31974247

RESUMEN

Single-cell RNA sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation is challenging. Here, we demonstrate a simple, yet robust, determinant of developmental potential-the number of expressed genes per cell-and leverage this measure of transcriptional diversity to develop a computational framework (CytoTRACE) for predicting differentiation states from scRNA-seq data. When applied to diverse tissue types and organisms, CytoTRACE outperformed previous methods and nearly 19,000 annotated gene sets for resolving 52 experimentally determined developmental trajectories. Additionally, it facilitated the identification of quiescent stem cells and revealed genes that contribute to breast tumorigenesis. This study thus establishes a key RNA-based feature of developmental potential and a platform for delineation of cellular hierarchies.


Asunto(s)
Diferenciación Celular/genética , Neoplasias/genética , ARN Citoplasmático Pequeño/genética , RNA-Seq/métodos , Análisis de la Célula Individual/métodos , Transcripción Genética , Animales , Secuencia de Bases , Variación Genética , Humanos , Ratones
3.
Nat Commun ; 8(1): 1669, 2017 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-29162812

RESUMEN

Previous studies have proposed that epithelial to mesenchymal transition (EMT) in breast cancer cells regulates metastasis, stem cell properties and chemo-resistance; most studies were based on in vitro culture of cell lines and mouse transgenic cancer models. However, the identity and function of cells expressing EMT-associated genes in normal murine mammary gland homeostasis and human breast cancer still remains under debate. Using in vivo lineage tracing and triple negative breast cancer (TNBC) patient derived xenografts we demonstrate that the repopulating capacity in normal mammary epithelial cells and tumorigenic capacity in TNBC is independent of expression of EMT-associated genes. In breast cancer, while a subset of cells with epithelial and mesenchymal phenotypes have stem cell activity, in many cells that have lost epithelial characteristics with increased expression of mesenchymal genes, have decreased tumor-initiating capacity and plasticity. These findings have implications for the development of effective therapeutic agents targeting tumor-initiating cells.


Asunto(s)
Mama/metabolismo , Transformación Celular Neoplásica/genética , Transición Epitelial-Mesenquimal/genética , Perfilación de la Expresión Génica , Neoplasias de la Mama Triple Negativas/genética , Animales , Mama/citología , Mama/fisiología , Células Epiteliales/metabolismo , Femenino , Humanos , Subunidad gamma Común de Receptores de Interleucina/deficiencia , Subunidad gamma Común de Receptores de Interleucina/genética , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Ratones Transgénicos , Regeneración/genética , Trasplante Heterólogo , Neoplasias de la Mama Triple Negativas/patología
4.
ACS Med Chem Lett ; 8(8): 869-874, 2017 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-28835804

RESUMEN

Histone lysine demethylases (KDMs) play a vital role in the regulation of chromatin-related processes. Herein, we describe our discovery of a series of potent KDM4 inhibitors that are both cell permeable and antiproliferative in cancer models. The modulation of histone H3K9me3 and H3K36me3 upon compound treatment was verified by homogeneous time-resolved fluorescence assay and by mass spectroscopy detection. Optimization of the series using structure-based drug design led to compound 6 (QC6352), a potent KDM4 family inhibitor that is efficacious in breast and colon cancer PDX models.

5.
Stem Cells ; 30(10): 2114-27, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22899386

RESUMEN

Poorly regulated tissue remodeling results in increased breast cancer risk, yet how breast cancer stem cells (CSC) participate in remodeling is unknown. We performed in vivo imaging of changes in fluorescent, endogenous duct architecture as a metric for remodeling. First, we quantitatively imaged physiologic remodeling of primary branches of the developing and regenerating mammary tree. To assess CSC-specific remodeling events, we isolated CSC from MMTV-Wnt1 (mouse mammary tumor virus long-term repeat enhancer driving Wnt1 oncogene) breast tumors, a well studied model in which tissue remodeling affects tumorigenesis. We confirm that CSC drive tumorigenesis, suggesting a link between CSC and remodeling. We find that normal, regenerating, and developing gland maintain a specific branching pattern. In contrast, transplantation of CSC results in changes in the branching patterns of endogenous ducts while non-CSC do not. Specifically, in the presence of CSC, we identified an increased number of branches, branch points, ducts which have greater than 40 branches (5/33 for CSC and 0/39 for non-CSC), and histological evidence of increased branching. Moreover, we demonstrate that only CSC implants invade into surrounding stroma with structures similar to developing mammary ducts (nine for CSC and one for non-CSC). Overall, we demonstrate a novel approach for imaging physiologic and pathological remodeling. Furthermore, we identify unique, CSC-specific, remodeling events. Our data suggest that CSC interact with the microenvironment differently than non-CSC, and that this could eventually be a therapeutic approach for targeting CSC.


Asunto(s)
Transformación Celular Neoplásica/patología , Neoplasias Mamarias Experimentales/patología , Células Madre Neoplásicas/ultraestructura , Animales , Transformación Celular Neoplásica/metabolismo , Epitelio/ultraestructura , Femenino , Colorantes Fluorescentes , Genes Reporteros , Proteínas Fluorescentes Verdes , Humanos , Procesamiento de Imagen Asistido por Computador , Neoplasias Mamarias Experimentales/metabolismo , Virus del Tumor Mamario del Ratón/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Imagen Molecular , Células Madre Neoplásicas/trasplante , Transducción de Señal , Microambiente Tumoral , Proteína Wnt1/metabolismo
6.
Lab Chip ; 9(10): 1365-70, 2009 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-19417902

RESUMEN

Chromatin immunoprecipitation (ChIP) is a powerful assay used to probe DNA-protein interactions. Traditional methods of implementing this assay are lengthy, cumbersome and require a large number of cells, making it difficult to study rare cell types such as certain cancer and stem cells. We have designed a microfluidic device to perform sensitive ChIP analysis on low cell numbers in a rapid, automated fashion while preserving the specificity of the assay. Comparing ChIP results for two modified histone protein targets, we showed our automated microfluidic ChIP (AutoChIP) from 2,000 cells to be comparable to that of conventional ChIP methods using 50,000-500,000 cells. This technology may provide a solution to the need for a high sensitivity, rapid, and automated ChIP assay, and in doing so facilitate the use of ChIP for many interesting and valuable applications.


Asunto(s)
Inmunoprecipitación de Cromatina , Técnicas Analíticas Microfluídicas , Animales , Automatización , Recuento de Células , Línea Celular Tumoral , Inmunoprecipitación de Cromatina/instrumentación , Inmunoprecipitación de Cromatina/métodos , Diseño de Equipo , Regulación Neoplásica de la Expresión Génica , Histonas/química , Ratones , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos
7.
Nature ; 458(7239): 780-3, 2009 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-19194462

RESUMEN

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.


Asunto(s)
Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/efectos de la radiación , Tolerancia a Radiación/fisiología , Especies Reactivas de Oxígeno/metabolismo , Animales , Neoplasias de la Mama/fisiopatología , Células Cultivadas , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Femenino , Expresión Génica , Humanos , Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/metabolismo , Ratones , Ratones Endogámicos C57BL
8.
Annu Rev Cell Dev Biol ; 23: 675-99, 2007.
Artículo en Inglés | MEDLINE | ID: mdl-17645413

RESUMEN

Cancers originally develop from normal cells that gain the ability to proliferate aberrantly and eventually turn malignant. These cancerous cells then grow clonally into tumors and eventually have the potential to metastasize. A central question in cancer biology is, which cells can be transformed to form tumors? Recent studies elucidated the presence of cancer stem cells that have the exclusive ability to regenerate tumors. These cancer stem cells share many characteristics with normal stem cells, including self-renewal and differentiation. With the growing evidence that cancer stem cells exist in a wide array of tumors, it is becoming increasingly important to understand the molecular mechanisms that regulate self-renewal and differentiation because corruption of genes involved in these pathways likely participates in tumor growth. This new paradigm of oncogenesis has been validated in a growing list of tumors. Studies of normal and cancer stem cells from the same tissue have shed light on the ontogeny of tumors. That signaling pathways such as Bmi1 and Wnt have similar effects in normal and cancer stem cell self-renewal suggests that common molecular pathways regulate both populations. Understanding the biology of cancer stem cells will contribute to the identification of molecular targets important for future therapies.


Asunto(s)
Células Madre Neoplásicas/citología , Células Madre Neoplásicas/fisiología , Animales , Sistema Nervioso Central/citología , Humanos , Ratones , Neoplasias/terapia , Transducción de Señal
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