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1.
Cell ; 186(25): 5569-5586.e21, 2023 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-38016469

RESUMEN

CD4+ T cells play fundamental roles in orchestrating immune responses and tissue homeostasis. However, our inability to associate peptide human leukocyte antigen class-II (HLA-II) complexes with their cognate T cell receptors (TCRs) in an unbiased manner has hampered our understanding of CD4+ T cell function and role in pathologies. Here, we introduce TScan-II, a highly sensitive genome-scale CD4+ antigen discovery platform. This platform seamlessly integrates the endogenous HLA-II antigen-processing machinery in synthetic antigen-presenting cells and TCR signaling in T cells, enabling the simultaneous screening of multiple HLAs and TCRs. Leveraging genome-scale human, virome, and epitope mutagenesis libraries, TScan-II facilitates de novo antigen discovery and deep exploration of TCR specificity. We demonstrate TScan-II's potential for basic and translational research by identifying a non-canonical antigen for a cancer-reactive CD4+ T cell clone. Additionally, we identified two antigens for clonally expanded CD4+ T cells in Sjögren's disease, which bind distinct HLAs and are expressed in HLA-II-positive ductal cells within affected salivary glands.


Asunto(s)
Linfocitos T CD4-Positivos , Epítopos de Linfocito T , Humanos , Células Presentadoras de Antígenos , Antígenos CD4/metabolismo , Antígenos HLA/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Línea Celular , Genoma Humano
2.
Cell ; 184(18): 4753-4771.e27, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34388391

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.


Asunto(s)
Inmunoterapia , Terapia Molecular Dirigida , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Aloinjertos/inmunología , Secuencias de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Antígeno B7-H1/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Sinergismo Farmacológico , Endocitosis/efectos de los fármacos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Humanos , Terapia de Inmunosupresión , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Ratones , Proteínas de Microfilamentos/química , Proteínas de Microfilamentos/metabolismo , Oncogenes , Organoides/efectos de los fármacos , Organoides/patología , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
3.
Annu Rev Cell Dev Biol ; 28: 599-625, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22881459

RESUMEN

Cell polarization is an evolutionarily conserved process that facilitates asymmetric distribution of organelles and proteins and that is modified dynamically during physiological processes such as cell division, migration, and morphogenesis. The plasticity with which cells change their behavior and phenotype in response to cell intrinsic and extrinsic cues is an essential feature of normal physiology. In disease states such as cancer, cells lose their ability to behave normally in response to physiological cues. A molecular understanding of mechanisms that alter the behavior of cancer cells is limited. Cell polarity proteins are a recognized class of molecules that can receive and interpret both intrinsic and extrinsic signals to modulate cell behavior. In this review, we discuss how cell polarity proteins regulate a diverse array of biological processes and how they can contribute to alterations in the behavior of cancer cells.


Asunto(s)
Polaridad Celular , Neoplasias/patología , Animales , División Celular , Proliferación Celular , Humanos , Proteínas de la Membrana/metabolismo , Morfogénesis , Complejos Multiproteicos/metabolismo , Neoplasias/metabolismo , Neoplasias/fisiopatología , Fenotipo , Transducción de Señal
4.
Nature ; 569(7755): 275-279, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30996345

RESUMEN

Drosophila Lgl and its mammalian homologues, LLGL1 and LLGL2, are scaffolding proteins that regulate the establishment of apical-basal polarity in epithelial cells1,2. Whereas Lgl functions as a tumour suppressor in Drosophila1, the roles of mammalian LLGL1 and LLGL2 in cancer are unclear. The majority (about 75%) of breast cancers express oestrogen receptors (ERs)3, and patients with these tumours receive endocrine treatment4. However, the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER+ disease4. Here we report that, unlike LLGL1, LLGL2 is overexpressed in ER+ breast cancer and promotes cell proliferation under nutrient stress. LLGL2 regulates cell surface levels of a leucine transporter, SLC7A5, by forming a trimeric complex with SLC7A5 and a regulator of membrane fusion, YKT6, to promote leucine uptake and cell proliferation. The oestrogen receptor targets LLGL2 expression. Resistance to endocrine treatment in breast cancer cells was associated with SLC7A5- and LLGL2-dependent adaption to nutrient stress. SLC7A5 was necessary and sufficient to confer resistance to tamoxifen treatment, identifying SLC7A5 as a potential therapeutic target for overcoming resistance to endocrine treatments in breast cancer. Thus, LLGL2 functions as a promoter of tumour growth and not as a tumour suppressor in ER+ breast cancer. Beyond breast cancer, adaptation to nutrient stress is critically important5, and our findings identify an unexpected role for LLGL2 in this process.


Asunto(s)
Neoplasias de la Mama/metabolismo , Proteínas del Citoesqueleto/metabolismo , Leucina/metabolismo , Receptores de Estrógenos/metabolismo , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estrógenos/farmacología , Femenino , Humanos , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Ratones , Proteínas R-SNARE/metabolismo
5.
Breast Cancer Res ; 26(1): 56, 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38553763

RESUMEN

Patient-derived organoid models of estrogen receptor-positive (ER+) breast cancer would provide a much-needed tool to understand drug resistance and disease progression better. However, the establishment and long-term maintenance of ER expression, function, and response in vitro remains a significant challenge. Here, we report the development of an ER+ breast tumor organoid medium (BTOM-ER) that conserves ER expression, estrogen responsiveness, and dependence, as well as sensitivity to endocrine therapy of ER+ patient-derived xenograft organoids (PDXO). Our findings demonstrate the utility of subtype-specific culture conditions that better mimic the characteristics of the breast epithelial biology and microenvironment, providing a powerful platform for investigating therapy response and disease progression of ER+ breast cancer.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Receptores de Estrógenos/metabolismo , Estrógenos , Organoides/metabolismo , Progresión de la Enfermedad , Microambiente Tumoral
6.
Cell ; 137(6): 1047-61, 2009 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-19524508

RESUMEN

Identification of bona fide tumor suppressors is often challenging because of the large number of genetic alterations present in most human cancers. To evaluate candidate genes present within chromosomal regions recurrently deleted in human cancers, we coupled high-resolution genomic analysis with a two-stage genetic study using RNA interference (RNAi). We found that Cyfip1, a subunit of the WAVE complex, which regulates cytoskeletal dynamics, is commonly deleted in human epithelial cancers. Reduced expression of CYFIP1 is commonly observed during invasion of epithelial tumors and is associated with poor prognosis in this setting. Silencing of Cyfip1 disturbed normal epithelial morphogenesis in vitro and cooperated with oncogenic Ras to produce invasive carcinomas in vivo. Mechanistically, we have linked alterations in WAVE-regulated actin dynamics with impaired cell-cell adhesion and cell-ECM interactions. Thus, we propose Cyfip1 as an invasion suppressor gene.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma/metabolismo , Invasividad Neoplásica , Animales , Carcinoma/diagnóstico , Carcinoma/patología , Línea Celular Tumoral , Células Cultivadas , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Queratinocitos/metabolismo , Ratones , Trasplante de Neoplasias , Trasplante Heterólogo
7.
Cancer Immunol Immunother ; 72(2): 301-313, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35834008

RESUMEN

BACKGROUND: Pancreatic cancer is a highly lethal malignancy often presenting with advanced disease and characterized by resistance to standard chemotherapy. Immune-based therapies such checkpoint inhibition have been largely ineffective such that pancreatic cancer is categorized as an immunologically "cold tumor". In the present study, we examine the therapeutic efficacy of a personalized cancer vaccine in which tumor cells are fused with dendritic cells (DC) resulting in the broad induction of antitumor immunity. RESULTS: In the KPC spontaneous pancreatic cancer murine model, we demonstrated that vaccination with DC/KPC fusions led to expansion of pancreatic cancer specific lymphocytes with an activated phenotype. Remarkably, vaccination led to a reduction in tumor bulk and near doubling of median survival in this highly aggressive model. In a second murine pancreatic model (Panc02), vaccination with DC/tumor fusions similarly led to expansion of tumor antigen specific lymphocytes and their infiltration to the tumor site. Having shown efficacy in immunocompetent murine models, we subsequently demonstrated that DC/tumor fusions generated from primary human pancreatic cancer and autologous DCs potently stimulate tumor specific cytotoxic lymphocyte responses. CONCLUSIONS: DC/tumor fusions induce the activation and expansion of tumor reactive lymphocytes with the capacity to infiltrate into the pancreatic cancer tumor bed.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias Pancreáticas , Humanos , Ratones , Animales , Activación de Linfocitos , Células Dendríticas , Neoplasias Pancreáticas
8.
Cell ; 135(5): 865-78, 2008 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-19041750

RESUMEN

Loss of cell polarity proteins such as Scribble induces neoplasia in Drosophila by promoting uncontrolled proliferation. In mammals, the role that polarity proteins play during tumorigenesis is not well understood. Here, we demonstrate that depletion of Scribble in mammary epithelia disrupts cell polarity, blocks three-dimensional morphogenesis, inhibits apoptosis, and induces dysplasia in vivo that progress to tumors after long latency. Loss of Scribble cooperates with oncogenes such as c-myc to transform epithelial cells and induce tumors in vivo by blocking activation of an apoptosis pathway. Like depletion, mislocalization of Scribble from cell-cell junction was sufficient to promote cell transformation. Interestingly, spontaneous mammary tumors in mice and humans possess both downregulated and mislocalized Scribble. Thus, we demonstrate that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death.


Asunto(s)
Neoplasias de la Mama/metabolismo , Polaridad Celular , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Mamarias Animales/metabolismo , Proteínas de la Membrana/genética , Proteínas Supresoras de Tumor/genética , Animales , Apoptosis , Línea Celular Tumoral , Regulación hacia Abajo , Células Epiteliales/citología , Humanos , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo
9.
PLoS Biol ; 16(6): e2004049, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29924804

RESUMEN

The contribution of basal and luminal cells to cancer progression and metastasis is poorly understood. We report generation of reporter systems driven by either keratin-14 (K14) or keratin-8 (K8) promoter that not only express a fluorescent protein but also an inducible suicide gene. Transgenic mice express the reporter genes in the right cell compartments of mammary gland epithelia and respond to treatment with toxins. In addition, we engineered the reporters into 4T1 metastatic mouse tumor cell line and demonstrate that K14+ cells, but not K14- or K8+, are both highly invasive in three-dimensional (3D) culture and metastatic in vivo. Treatment of cells in culture, or tumors in mice, with reporter-targeting toxin inhibited both invasive behavior and metastasis in vivo. RNA sequencing (RNA-seq), secretome, and epigenome analysis of K14+ and K14- cells led to the identification of amphoterin-induced protein 2 (Amigo2) as a new cell invasion driver whose expression correlated with decreased relapse-free survival in patients with TP53 wild-type (WT) breast cancer.


Asunto(s)
Genes Reporteros/genética , Glándulas Mamarias Animales/patología , Neoplasias Mamarias Animales/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Animales , División Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Células Epiteliales/patología , Femenino , Proteínas Fluorescentes Verdes/genética , Queratina-14/genética , Queratina-8/genética , Glándulas Mamarias Animales/citología , Neoplasias Mamarias Animales/genética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Metástasis de la Neoplasia/patología , Regiones Promotoras Genéticas/genética
10.
Biochim Biophys Acta Rev Cancer ; 1869(2): 103-116, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29369778

RESUMEN

Cell polarity is a fundamental property used to generate asymmetry and structure in all cells. Cancer is associated with loss of cell and tissue structure. While observations made in model system such as Drosophila, identify polarity regulators as tumor suppressors that cause inappropriate cell division, studies in mammalian epithelia do not always support such a causative contribution. Our analysis of published cancer dataset shows that many polarity genes, including PARD6B, SCRIB, PRKCI, DLG1, DLG2, DLG5 and LLGL2, are frequently amplified in multiple cancers raising the possibility that mammalian epithelia may have evolved to use polarity proteins in multiple ways where they may have tumor promoting functions. In this review, we reinterpret the published results and propose a modified perspective for the role of polarity regulators in cancer biology. In addition to the traditional form of cell polarity, which is involved establishment of maintenance of normal cell structure and asymmetry, we propose that some mammalian polarity proteins also regulate subcellular polarity (intracellular asymmetry), which can improve cellular fitness to carry out functions such as proliferation, apoptosis, stress adaptation, stemness and organelle biology. Here, we define subcellular polarity and discuss evidence that supports a role for subcellular polarity in biology.


Asunto(s)
Polaridad Celular , Proliferación Celular , Transformación Celular Neoplásica/patología , Células Epiteliales/patología , Neoplasias/patología , Animales , Supervivencia Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Células Epiteliales/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Transducción de Señal , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
11.
Development ; 144(6): 963-967, 2017 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-28292842

RESUMEN

From October 12-15th, 2016, EMBO∣EMBL held a symposium to bring together those in the scientific community with a shared interest in using three-dimensional (3D) culture methods to study biology, model disease and personalize treatments. The symposium, entitled 'Organoids: modelling organ development and disease in 3D culture', which was organized by Juergen Knoblich, Mina Bissell and Esther Schnapp, was particularly timely as there were otherwise few opportunities for those interested in using 3D culture platforms to interact outside of their organ-specific scientific community. The meeting was a fantastic success, creating a lot of discussion and cross-fertilization of ideas from developmental biologists to bioengineers and biophysicists. This Meeting Review provides a summary of the talks presented and the major themes that emerged from the symposium.


Asunto(s)
Biología Evolutiva , Organoides/fisiología , Animales , Bioingeniería , Humanos , Ratones , Modelos Biológicos , Especificidad de Órganos
12.
Mol Cell ; 47(3): 469-83, 2012 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-22883624

RESUMEN

Cell polarity plays a key role in development and is disrupted in tumors, yet the molecules and mechanisms that regulate polarity remain poorly defined. We found that the scaffolding adaptor GAB1 interacts with two polarity proteins, PAR1 and PAR3. GAB1 binds PAR1 and enhances its kinase activity. GAB1 brings PAR1 and PAR3 into a transient complex, stimulating PAR3 phosphorylation by PAR1. GAB1 and PAR6 bind the PAR3 PDZ1 domain and thereby compete for PAR3 binding. Consequently, GAB1 depletion causes PAR3 hypophosphorylation and increases PAR3/PAR6 complex formation, resulting in accelerated and enhanced tight junction formation, increased transepithelial resistance, and lateral domain shortening. Conversely, GAB1 overexpression, in a PAR1/PAR3-dependent manner, disrupts epithelial apical-basal polarity, promotes multilumen cyst formation, and enhances growth factor-induced epithelial cell scattering. Our results identify GAB1 as a negative regulator of epithelial cell polarity that functions as a scaffold for modulating PAR protein complexes on the lateral membrane.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Polaridad Celular/genética , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Células CACO-2 , Proteínas de Ciclo Celular/genética , Perros , Células HEK293 , Humanos , Riñón/citología , Proteínas de la Membrana/genética , Ratones , Fosfoproteínas/genética , Unión Proteica/genética , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Estructura Terciaria de Proteína/genética
13.
Genes Dev ; 26(20): 2253-8, 2012 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-23070811

RESUMEN

Prolactin (PRL) is a peptide hormone that is produced by the pituitary gland and is known to regulate lactogenic differentiation. There is a significant body of evidence that points to autocrine production of prolactin and activation of an autocrine/paracrine signaling pathway to regulate cell proliferation and migration and inhibition of cell death. This perspective highlights the recent study in the October 1, 2012, issue of Genes & Development by Chen and colleagues (pp. 2154-2168) that describes a mechanism for autocrine prolactin production and places the finding in the context of a role for prolactin in breast development and cancer.


Asunto(s)
Regulación de la Expresión Génica , Lactancia/fisiología , Prolactina/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT5/metabolismo , Animales , Femenino , Embarazo
14.
Genes Dev ; 25(13): 1412-25, 2011 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-21724833

RESUMEN

We used an RNAi-mediated loss-of-function screen to study systematically the role of the protein tyrosine phosphatase (PTP) superfamily of enzymes in mammary epithelial cell motility in the absence or presence of the oncoprotein tyrosine kinase ERBB2. We report that although shRNAs directed against most of the PTP family were without effect, suppression of three PTPs-PRPN23, PTPRG, and PTPRR-enhanced cell motility. Furthermore, we found that suppression of PTPN23, but not PTPRG or PTPRR, induced cell invasion. Suppression of PTPN23 increased E-cadherin internalization, impaired early endosome trafficking of E-cadherin, induced the expression of mesenchymal proteins, and caused cell scattering. The activity of SRC and ß-catenin was elevated when PTPN23 was suppressed. Moreover, we identified SRC, E-cadherin, and ß-catenin as direct substrates of PTPN23. Inhibition of SRC with the small molecular inhibitor SU6656 blocked the effects of PTPN23 depletion. These findings suggest that loss of PTPN23 may increase the activity of SRC and the phosphorylation status of the E-cadherin/ß-catenin signaling complex to promote tumor growth and invasive behavior in breast cancer. In addition, our studies highlight functional specificity among PTPs and reveal new roles for PTPs in mammary epithelial cell biology.


Asunto(s)
Glándulas Mamarias Humanas/citología , Glándulas Mamarias Humanas/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Cadherinas/metabolismo , Caveolina 1/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular , Endocitosis , Endosomas/metabolismo , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Invasividad Neoplásica , Transporte de Proteínas , Proteínas Tirosina Fosfatasas no Receptoras/genética , Interferencia de ARN , Receptor ErbB-2/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Proteínas Tirosina Fosfatasas Clase 7 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 7 Similares a Receptores/metabolismo , Transducción de Señal
15.
Biophys J ; 115(10): 2067-2077, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30366626

RESUMEN

Epithelial-to-mesenchymal transition (EMT) and maturation of collagen fibrils in the tumor microenvironment play a significant role in cancer cell invasion and metastasis. Confinement along fiber-like tracks enhances cell migration. To what extent and in what manner EMT further promotes migration in a microenvironment already conducive to migration is poorly understood. Here, we show that TGFß-mediated EMT significantly enhances migration on fiber-like micropatterned tracks of collagen, doubling migration speed and tripling persistence relative to untreated mammary epithelial cells. Thus, cell-intrinsic EMT and extrinsic fibrillar tracks have nonredundant effects on motility. To better understand EMT-enhanced fibrillar migration, we investigated the regulation of Golgi positioning, which is involved in front-rear polarization and persistent cell migration. Confinement along fiber-like tracks has been reported to favor posterior Golgi positioning, whereas anterior positioning is observed during 2-day wound healing. Although EMT also regulates cell polarity, little is known about its effect on Golgi positioning. Here, we show that EMT induces a 2:1 rearward bias in Golgi positioning; however, positional bias explains less than 2% of single-cell variability in migration speed and persistence. Meanwhile, EMT significantly stabilizes Golgi positioning. Cells that enhance migration in response to TGFß maintain Golgi position for 2- to 4-fold longer than nonresponsive counterparts irrespective of whether the Golgi is ahead or behind the nucleus. In fact, 28% of TGFß-responsive cells exhibit a fully committed Golgi phenotype with the organelle either in the anterior or posterior position for over 90% of the time. Furthermore, single-cell differences in Golgi stability capture up to 18% of variations in migration speed. These results suggest a hypothesis that the Golgi may be part of a core physical scaffold that affects how cell-generated forces are distributed during migration. A stable scaffold would be expected to more consistently and therefore more productively distribute forces over time, leading to efficient migration.


Asunto(s)
Movimiento Celular , Transición Epitelial-Mesenquimal , Aparato de Golgi/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Colágeno/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Aparato de Golgi/efectos de los fármacos , Humanos , Factor de Crecimiento Transformador beta/farmacología
16.
J Cell Sci ; 129(12): 2307-15, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27179074

RESUMEN

The cell polarity protein scribble (SCRIB) is a crucial regulator of polarization, cell migration and tumorigenesis. Whereas SCRIB is known to regulate early stages of mouse mammary gland development, its function in the adult gland is not known. Using an inducible RNA interference (RNAi) mouse model for downregulating SCRIB expression, we report an unexpected role for SCRIB as a positive regulator of cell proliferation during pregnancy-associated mammary alveologenesis. SCRIB was required in the epithelial cell compartment of the mammary gland. Lack of SCRIB attenuated prolactin-induced activation of the JAK2-STAT5 signaling pathway. In addition, loss of SCRIB resulted in the downregulation of prolactin receptor (PRLR) at cell surface and its accumulation in intracellular structures that express markers of the Golgi complex and the recycling endosome. Unlike its role in virgin gland as a negative regulator cell proliferation, SCRIB is a positive regulator of mammary epithelial cell proliferation during pregnancy.


Asunto(s)
Envejecimiento/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Glándulas Mamarias Animales/crecimiento & desarrollo , Glándulas Mamarias Animales/metabolismo , Organogénesis , Animales , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Janus Quinasa 2/metabolismo , Glándulas Mamarias Animales/efectos de los fármacos , Ratones , Organogénesis/efectos de los fármacos , Embarazo , Prolactina/farmacología , Receptores de Prolactina/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal/efectos de los fármacos
17.
Genes Dev ; 24(9): 947-56, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20439433

RESUMEN

The loss of epithelial polarity is thought to play an important role during mammary tumor progression. Using a unique transgenic mouse model of ErbB2-induced mammary tumorigenesis, we demonstrated previously that amplification of ErbB2 is frequently accompanied by loss of the 14-3-3sigma gene. Here, we demonstrate that ectopic expression of 14-3-3sigma results in restoration of epithelial polarity in ErbB2-transformed mammary tumor cells. We further demonstrate that targeted deletion of 14-3-3sigma within primary mammary epithelial cells increases their proliferative capacity and adversely affects their ability to form polarized structures. Finally, we show that 14-3-3sigma can specifically form complexes with Par3, a protein that is essential for the maintenance of a polarized epithelial state. Taken together, these observations suggest that 14-3-3sigma plays a critical role in retaining epithelial polarity.


Asunto(s)
Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Polaridad Celular/genética , Células Epiteliales/citología , Animales , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Uniones Intercelulares/genética , Glándulas Mamarias Animales/citología , Ratones , Ratones Noqueados
18.
Proc Natl Acad Sci U S A ; 111(11): 4191-6, 2014 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-24599592

RESUMEN

Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer in women and lacks an effective targeted therapy. Therefore, finding common vulnerabilities in these tumors represents an opportunity for more effective treatment. Despite the growing appreciation of G-protein-coupled receptor (GPCR)-mediated signaling in cancer pathogenesis, very little is known about the role GPCRs play in TNBC. Using genomic information of human breast cancer, we have discovered that the orphan GPCR, G-protein-coupled receptor 161 (GPR161) is overexpressed specifically in TNBC and correlates with poor prognosis. Knockdown of GPR161 impairs proliferation of human basal breast cancer cell lines. Overexpression of GPR161 in human mammary epithelial cells increases cell proliferation, migration, intracellular accumulation of E-cadherin, and formation of multiacinar structures in 3D culture. GPR161 forms a signaling complex with the scaffold proteins ß-arrestin 2 and Ile Gln motif containing GTPase Activating Protein 1, a regulator of mammalian target of rapamycin complex 1 and E-cadherin. Consistently, GPR161 amplified breast tumors and cells overexpressing GPR161 activate mammalian target of rapamycin signaling and decrease Ile Gln motif containing GTPase Activating Protein 1 phosphorylation. Thus, we identify the orphan GPCR, GPR161, as an important regulator and a potential drug target for TNBC.


Asunto(s)
Neoplasias de la Mama/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Secuencia de Bases , Neoplasias de la Mama/genética , Proliferación Celular , Electroforesis en Gel de Poliacrilamida , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Vectores Genéticos/genética , Humanos , Indoles , Datos de Secuencia Molecular , Invasividad Neoplásica/genética , Retroviridae
19.
Australas Psychiatry ; 25(3): 262-265, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28135805

RESUMEN

OBJECTIVE: Many models of community-based mental health crisis teams have been reported. We present our experience of an outreach team made up of a paramedic and mental health nurse. METHODS: A proof-of-concept was conducted in Western Sydney. The primary outcome was the proportion of patients where the team were able to facilitate the most appropriate care. RESULTS: Nearly 70% of patients were able to be treated outside the Emergency Department, with about two-thirds being transported directly to a mental health facility. CONCLUSION: We have demonstrated that our model of care is successful in enabling appropriate physical and mental health care for patients suffering an acute mental health crisis.


Asunto(s)
Servicios Comunitarios de Salud Mental , Servicios de Urgencia Psiquiátrica , Trastornos Mentales/terapia , Grupo de Atención al Paciente , Transporte de Pacientes , Adulto , Técnicos Medios en Salud , Femenino , Humanos , Colaboración Intersectorial , Masculino , Persona de Mediana Edad , Nueva Gales del Sur , Enfermeras y Enfermeros , Prueba de Estudio Conceptual
20.
Biophys J ; 110(8): 1886-1895, 2016 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-27119647

RESUMEN

The breast tumor microenvironment (TMEN) is a unique niche where protein fibers help to promote invasion and metastasis. Cells migrating along these fibers are constantly interacting with each other. How cells respond to these interactions has important implications. Cancer cells that circumnavigate or slide around other cells on protein fibers take a less tortuous path out of the primary tumor; conversely, cells that turn back upon encountering other cells invade less efficiently. The contact response of migrating cancer cells in a fibrillar TMEN is poorly understood. Here, using high-aspect ratio micropatterns as a model fibrillar platform, we show that metastatic cells overcome spatial constraints to slide effectively on narrow fiber-like dimensions, whereas nontransformed MCF-10A mammary epithelial cells require much wider micropatterns to achieve moderate levels of sliding. Downregulating the cell-cell adhesion protein, E-cadherin, enables MCF-10A cells to slide on narrower micropatterns; meanwhile, introducing exogenous E-cadherin in metastatic MDA-MB-231 cells increases the micropattern dimension at which they slide. We propose the characteristic fibrillar dimension (CFD) at which effective sliding is achieved as a metric of sliding ability under spatial confinement. Using this metric, we show that metastasis-promoting genetic perturbations enhance cell sliding and reduce CFD. Activation of ErbB2 combined with downregulation of the tumor suppressor and cell polarity regulator, PARD3, reduced the CFD, in agreement with their cooperative role in inducing metastasis in vivo. The CFD was further reduced by a combination of ErbB2 activation and transforming growth factor ß stimulation, which is known to enhance invasive behavior. These findings demonstrate that sliding is a quantitative property and a decrease in CFD is an effective metric to understand how multiple genetic hits interact to change cell behavior in fibrillar environments. This quantitative framework sheds insights into how genetic perturbations conspire with fibrillar maturation in the TMEN to drive the invasive behavior of cancer cells.


Asunto(s)
Neoplasias de la Mama/patología , Movimiento Celular , Modelos Biológicos , Proteínas Adaptadoras Transductoras de Señales , Cadherinas/deficiencia , Cadherinas/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Proteínas de la Membrana/metabolismo , Metástasis de la Neoplasia , Receptor ErbB-2/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Microambiente Tumoral/efectos de los fármacos
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