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1.
Nature ; 2020 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-31959985

RESUMEN

Single-cell analyses have revealed extensive heterogeneity between and within human tumours1-4, but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry5 to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.

2.
J Clin Invest ; 128(10): 4525-4542, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30222135

RESUMEN

The E3 ubiquitin ligase RNF8 plays critical roles in maintaining genomic stability by promoting the repair of DNA double-strand breaks (DSBs) through ubiquitin signaling. Abnormal activation of Notch signaling and defective repair of DSBs promote breast cancer risk. Here, we found that low expression of the full-length RNF8 correlated with poor prognosis for breast cancer patients. Our data revealed that in addition to its role in the repair of DSBs, RNF8 regulated Notch1 signaling and cell-fate determination of mammary luminal progenitors. Mechanistically, RNF8 acted as a negative regulator of Notch signaling by ubiquitylating the active NOTCH1 protein (N1ICD), leading to its degradation. Consistent with abnormal activation of Notch signaling and impaired repair of DSBs in Rnf8-mutant mammary epithelial cells, we observed increased risk of mammary tumorigenesis in mouse models for RNF8 deficiency. Notably, deficiency of RNF8 sensitized breast cancer cells to combination of pharmacological inhibitors of Notch signaling and poly(ADP-ribose) polymerase (PARP), suggesting implications for treatment of breast cancer associated with impaired RNF8 expression or function.


Asunto(s)
Carcinogénesis/metabolismo , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/metabolismo , Proteínas de Neoplasias/metabolismo , Receptor Notch1/metabolismo , Transducción de Señal , Ubiquitina-Proteína Ligasas/biosíntesis , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Roturas del ADN de Doble Cadena , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Animales/genética , Neoplasias Mamarias Animales/patología , Ratones , Ratones Noqueados , Proteínas de Neoplasias/genética , Receptor Notch1/genética , Ubiquitina-Proteína Ligasas/genética
3.
Nat Methods ; 14(9): 873-876, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28783155

RESUMEN

Single-cell, spatially resolved omics analysis of tissues is poised to transform biomedical research and clinical practice. We have developed an open-source, computational histology topography cytometry analysis toolbox (histoCAT) to enable interactive, quantitative, and comprehensive exploration of individual cell phenotypes, cell-cell interactions, microenvironments, and morphological structures within intact tissues. We highlight the unique abilities of histoCAT through analysis of highly multiplexed mass cytometry images of human breast cancer tissues.


Asunto(s)
Comunicación Celular/fisiología , Citometría de Flujo/métodos , Imagen Molecular/métodos , Proteoma/metabolismo , Programas Informáticos , Análisis de Matrices Tisulares/métodos , Algoritmos , Interpretación de Imagen Asistida por Computador/métodos , Interfaz Usuario-Computador
4.
Nat Rev Cancer ; 17(1): 38-53, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27932800

RESUMEN

A compelling long-term goal of cancer biology is to understand the crucial players during tumorigenesis in order to develop new interventions. Here, we review how the four non-redundant tissue inhibitors of metalloproteinases (TIMPs) regulate the pericellular proteolysis of a vast range of matrix and cell surface proteins, generating simultaneous effects on tumour architecture and cell signalling. Experimental studies demonstrate the contribution of TIMPs to the majority of cancer hallmarks, and human cancers invariably show TIMP deregulation in the tumour or stroma. Of the four TIMPs, TIMP1 overexpression or TIMP3 silencing is consistently associated with cancer progression or poor patient prognosis. Future efforts will align mouse model systems with changes in TIMPs in patients, will delineate protease-independent TIMP function, will pinpoint therapeutic targets within the TIMP-metalloproteinase-substrate network and will use TIMPs in liquid biopsy samples as biomarkers for cancer prognosis.


Asunto(s)
Neoplasias/metabolismo , Neoplasias/fisiopatología , Inhibidores Tisulares de Metaloproteinasas/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/fisiología , Humanos , Proteolisis , Transducción de Señal , Inhibidores Tisulares de Metaloproteinasas/fisiología , Microambiente Tumoral/fisiología
5.
Mol Cell Oncol ; 3(3): e975082, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27314104

RESUMEN

The tumor stroma has the capacity to drive cancer progression, although the mechanisms governing these effects are incompletely understood. Recently, we reported that deletion of tissue inhibitor of metalloproteinases (Timps) in fibroblasts unleashes the function of cancer-associated fibroblasts and identifies a novel mode of stromal-tumor communication that activates key oncogenic pathways invoving Notch and ras homolog gene family, member A (RhoA) via stromal exosomes.

6.
Stem Cell Reports ; 5(1): 31-44, 2015 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-26095608

RESUMEN

Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells.


Asunto(s)
Glándulas Mamarias Animales/metabolismo , Receptor Activador del Factor Nuclear kappa-B/genética , Células Madre/citología , Trombospondinas/genética , Animales , Proliferación Celular/genética , Femenino , Humanos , Glándulas Mamarias Animales/crecimiento & desarrollo , Ratones , Receptor Activador del Factor Nuclear kappa-B/antagonistas & inhibidores , Trombospondinas/biosíntesis , Vía de Señalización Wnt/genética
7.
PLoS One ; 10(3): e0120107, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25807548

RESUMEN

Timp3 is commonly silenced in breast cancer, but mechanistic studies have identified both tumor promotion and suppression effects of this gene. We have taken a genetic approach to determine the impact of Timp3 loss on two mouse models of breast cancer. Interestingly, MMTV-PyMT Timp3-/- mice have delayed tumor onset and 36% of MMTV-Neu Timp3-/- mice remain tumor free. TIMP3 is a regulator of TNF signaling and similar to Timp3, Tnf or Tnfr1 loss delays early tumorigenesis. The tumor suppression in Timp3 null mice requires Tnfr1, but does not result in alterations in the local immune compartment. In the mammary gland, Timps are highly expressed in the stroma and through the transplantation of tumor cells we observe that Timp3 deficiency in the host is sufficient to delay the growth of early, but not advanced tumor cells. Together our data is the first to identify a tumor promoting role of endogenous Timp3 in vivo, the spatial and temporal windows of this effect, and its dependence on Tnfr1.


Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/genética , Inhibidor Tisular de Metaloproteinasa-3/deficiencia , Inhibidor Tisular de Metaloproteinasa-3/genética , Animales , Transformación Celular Neoplásica/patología , Femenino , Masculino , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/genética , Factor de Necrosis Tumoral alfa/genética
8.
Nat Cell Biol ; 17(3): 217-27, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25706237

RESUMEN

Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cell-extrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11-fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp1/Timp3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model.


Asunto(s)
Envejecimiento/genética , Proliferación Celular/genética , Glándulas Mamarias Animales/citología , Células Madre/citología , Inhibidor Tisular de Metaloproteinasa-1/genética , Inhibidor Tisular de Metaloproteinasa-3/genética , Factores de Edad , Envejecimiento/metabolismo , Animales , Diferenciación Celular , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/metabolismo , Ratones , Ratones Noqueados , Mitosis , Receptores Notch/genética , Receptores Notch/metabolismo , Factores de Riesgo , Transducción de Señal , Huso Acromático/metabolismo , Huso Acromático/patología , Células Madre/metabolismo , Inhibidor Tisular de Metaloproteinasa-1/deficiencia , Inhibidor Tisular de Metaloproteinasa-3/deficiencia
9.
Stem Cell Reports ; 4(3): 313-322, 2015 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-28447939

RESUMEN

Progesterone drives mammary stem and progenitor cell dynamics through paracrine mechanisms that are currently not well understood. Here, we demonstrate that CXCR4, the receptor for stromal-derived factor 1 (SDF-1; CXC12), is a crucial instructor of hormone-induced mammary stem and progenitor cell function. Progesterone elicits specific changes in the transcriptome of basal and luminal mammary epithelial populations, where CXCL12 and CXCR4 represent a putative ligand-receptor pair. In situ, CXCL12 localizes to progesterone-receptor-positive luminal cells, whereas CXCR4 is induced in both basal and luminal compartments in a progesterone-dependent manner. Pharmacological inhibition of CXCR4 signaling abrogates progesterone-directed expansion of basal (CD24+CD49fhi) and luminal (CD24+CD49flo) subsets. This is accompanied by a marked reduction in CD49b+SCA-1- luminal progenitors, their functional capacity, and lobuloalveologenesis. These findings uncover CXCL12 and CXCR4 as novel paracrine effectors of hormone signaling in the adult mammary gland, and present a new avenue for potentially targeting progenitor cell growth and malignant transformation in breast cancer.

10.
Nat Cell Biol ; 16(9): 889-901, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25150980

RESUMEN

Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.


Asunto(s)
Fibroblastos/metabolismo , Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/patología , Inhibidores Tisulares de Metaloproteinasas/genética , Proteínas ADAM/metabolismo , Proteína ADAM10 , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Línea Celular Tumoral , Movimiento Celular , Exosomas/fisiología , Femenino , Fibroblastos/patología , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Mamarias Experimentales/enzimología , Proteínas de la Membrana/metabolismo , Metaloendopeptidasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Trasplante de Neoplasias , Fenotipo , Transducción de Señal , Inhibidores Tisulares de Metaloproteinasas/deficiencia , Carga Tumoral
11.
PLoS One ; 6(10): e26718, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22053204

RESUMEN

Post-lactation mammary involution is a homeostatic process requiring epithelial apoptosis and clearance. Given that the deficiency of the extracellular metalloproteinase inhibitor TIMP3 impacts epithelial apoptosis and heightens inflammatory response, we investigated whether TIMP3 regulates these distinct processes during the phases of mammary gland involution in the mouse. Here we show that TIMP3 deficiency leads to TNF dysregulation, earlier caspase activation and onset of mitochondrial apoptosis. This accelerated first phase of involution includes faster loss of initiating signals (STAT3 activation; TGFß3) concurrent with immediate luminal deconstruction through E-cadherin fragmentation. Epithelial apoptosis is followed by accelerated adipogenesis and a greater macrophage and T-cell infiltration in Timp3(-/-) involuting glands. Crossing in Tnf deficiency abrogates caspase 3 activation, but heightens macrophage and T-cell influx into Timp3(-/-) glands. The data indicate that TIMP3 differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution. An understanding of the molecular factors and wound healing microenvironment of the postpartum mammary gland may have implications for understanding pregnancy-associated breast cancer risk.


Asunto(s)
Apoptosis , Células Epiteliales/inmunología , Células Epiteliales/patología , Linfocitos/inmunología , Glándulas Mamarias Animales/patología , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Uniones Adherentes/efectos de los fármacos , Uniones Adherentes/metabolismo , Adipogénesis/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Cadherinas/metabolismo , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/enzimología , Femenino , Humanos , Inflamación/patología , Linfocitos/efectos de los fármacos , Glándulas Mamarias Animales/enzimología , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Proteínas Recombinantes/farmacología , Transducción de Señal/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-3/deficiencia
12.
Nature ; 465(7299): 803-7, 2010 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-20445538

RESUMEN

Reproductive history is the strongest risk factor for breast cancer after age, genetics and breast density. Increased breast cancer risk is entwined with a greater number of ovarian hormone-dependent reproductive cycles, yet the basis for this predisposition is unknown. Mammary stem cells (MaSCs) are located within a specialized niche in the basal epithelial compartment that is under local and systemic regulation. The emerging role of MaSCs in cancer initiation warrants the study of ovarian hormones in MaSC homeostasis. Here we show that the MaSC pool increases 14-fold during maximal progesterone levels at the luteal dioestrus phase of the mouse. Stem-cell-enriched CD49fhi cells amplify at dioestrus, or with exogenous progesterone, demonstrating a key role for progesterone in propelling this expansion. In aged mice, CD49fhi cells display stasis upon cessation of the reproductive cycle. Progesterone drives a series of events where luminal cells probably provide Wnt4 and RANKL signals to basal cells which in turn respond by upregulating their cognate receptors, transcriptional targets and cell cycle markers. Our findings uncover a dynamic role for progesterone in activating adult MaSCs within the mammary stem cell niche during the reproductive cycle, where MaSCs are putative targets for cell transformation events leading to breast cancer.


Asunto(s)
Envejecimiento/fisiología , Glándulas Mamarias Animales/citología , Progesterona/farmacología , Células Madre/citología , Células Madre/efectos de los fármacos , Animales , Recuento de Células , División Celular/efectos de los fármacos , Transformación Celular Neoplásica , Estrógenos/farmacología , Ciclo Estral/sangre , Ciclo Estral/fisiología , Femenino , Homeostasis/efectos de los fármacos , Integrina alfa6/metabolismo , Ratones , Ovariectomía , Comunicación Paracrina/efectos de los fármacos , Progesterona/sangre , Progesterona/metabolismo , Ligando RANK/metabolismo , Receptores Estrogénicos/metabolismo , Receptores de Progesterona/metabolismo , Nicho de Células Madre/citología , Nicho de Células Madre/efectos de los fármacos , Nicho de Células Madre/metabolismo , Células Madre/metabolismo , Proteínas Wnt/metabolismo , Proteína Wnt4
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