Epithelial Cell Biology Group

Madrid, Spain

Epithelial Cell Biology Group

Madrid, Spain

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Perez-Moreno M.,Epithelial Cell Biology Group
Nature Reviews Cancer | Year: 2012

After years of extensive scientific discovery much has been learned about the networks that regulate epithelial homeostasis. Loss of expression or functional activity of cell adhesion and cell polarity proteins (including the PAR, crumbs (CRB) and scribble (SCRIB) complexes) is intricately related to advanced stages of tumour progression and invasiveness. But the key roles of these proteins in crosstalk with the Hippo and liver kinase B1 (LKB1)-AMPK pathways and in epithelial function and proliferation indicate that they may also be associated with the early stages of tumorigenesis. For example, deregulation of adhesion and polarity proteins can cause misoriented cell divisions and increased self-renewal of adult epithelial stem cells. In this Review, we highlight some advances in the understanding of how loss of epithelial cell polarity contributes to tumorigenesis. © 2012 Macmillan Publishers Limited. All rights reserved.


Sanchez-Martinez R.,IMDEA Madrid Institute for Advanced Studies | Cruz-Gil S.,IMDEA Madrid Institute for Advanced Studies | de Cedron M.G.,IMDEA Madrid Institute for Advanced Studies | Alvarez-Fernandez M.,Cell Division and Cancer Group | And 11 more authors.
Oncotarget | Year: 2015

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/ stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.


Epifano C.,Epithelial Cell Biology Group | Megias D.,Confocal Microscopy Core Unit | Perez-Moreno M.,Epithelial Cell Biology Group
EMBO Reports | Year: 2014

The adherens junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120 catenin regulates the intrinsic migratory properties of primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via an increase in actin stress fibers, reduction in integrin turnover and an increase in the robustness of focal adhesions. The other is coupled to the secretion of inflammatory cytokines including interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer. Synopsis The adherens junction protein p120-catenin differentially regulates the migratory behavior of primary epidermal cells via RhoA-GTPase-mediated signaling. Loss of p120-catenin restricts single cell migration intrinsically and at the same time increases the migratory behavior of neighboring cells during wound repair. Loss of p120-catenin decreases cell migration in single primary epidermal cells as a consequence of increased actin stress fibers, focal adhesion robustness and reduced integrin turnover. The restrain in cell motility is counteracted by the secretion of inflammatory factors to the environment, including IL-24, which enhances the migration of neighboring epidermal cells. The adherens junction protein p120-catenin differentially regulates the migratory behavior of primary epidermal cells via RhoA-GTPase-mediated signaling. Loss of p120-catenin restricts single cell migration intrinsically and at the same time increases the migratory behavior of neighboring cells during wound repair. © 2014 The Authors.


PubMed | La Paz University Hospital Idi, IMDEA Madrid Institute for Advanced Studies, Epithelial Cell Biology Group and Cell Division and Cancer Group
Type: Journal Article | Journal: Oncotarget | Year: 2015

The alterations in carbohydrate metabolism that fuel tumor growth have been extensively studied. However, other metabolic pathways involved in malignant progression, demand further understanding. Here we describe a metabolic acyl-CoA synthetase/stearoyl-CoA desaturase ACSL/SCD network causing an epithelial-mesenchymal transition (EMT) program that promotes migration and invasion of colon cancer cells. The mesenchymal phenotype produced upon overexpression of these enzymes is reverted through reactivation of AMPK signaling. Furthermore, this network expression correlates with poorer clinical outcome of stage-II colon cancer patients. Finally, combined treatment with chemical inhibitors of ACSL/SCD selectively decreases cancer cell viability without reducing normal cells viability. Thus, ACSL/SCD network stimulates colon cancer progression through conferring increased energetic capacity and invasive and migratory properties to cancer cells, and might represent a new therapeutic opportunity for colon cancer treatment.


Castellana D.,Epithelial Cell Biology Group | Paus R.,University of Manchester | Paus R.,University of Munster | Perez-Moreno M.,Epithelial Cell Biology Group
PLoS Biology | Year: 2014

Skin epithelial stem cells operate within a complex signaling milieu that orchestrates their lifetime regenerative properties. The question of whether and how immune cells impact on these stem cells within their niche is not well understood. Here we show that skin-resident macrophages decrease in number because of apoptosis before the onset of epithelial hair follicle stem cell activation during the murine hair cycle. This process is linked to distinct gene expression, including Wnt transcription. Interestingly, by mimicking this event through the selective induction of macrophage apoptosis in early telogen, we identify a novel involvement of macrophages in stem cell activation in vivo. Importantly, the macrophage-specific pharmacological inhibition of Wnt production delays hair follicle growth. Thus, perifollicular macrophages contribute to the activation of skin epithelial stem cells as a novel, additional cue that regulates their regenerative activity. This finding may have translational implications for skin repair, inflammatory skin diseases and cancer. © 2014 Castellana et al.


PubMed | Experimental Oncology Group and Epithelial Cell Biology Group
Type: | Journal: Journal of cell science | Year: 2017

Epidermal homeostasis is tightly controlled by a balancing act of self-renewal or terminal differentiation of proliferating basal keratinocytes. An increase in DNA content as a consequence of a mitotic block is a recognized mechanism underlying keratinocyte differentiation, but the molecular mechanisms involved in this process are not yet fully understood. Using cultured primary keratinocytes, here we report that the expression of the mammalian Microtubule and Kinetochore-associated protein Clasp2 is intimately associated to the basal proliferative makeup of keratinocytes, and its deficiency leads to premature differentiation. Clasp2 deficient keratinocytes exhibit increased centrosomal numbers, and numerous mitotic alterations, including multipolar spindles and chromosomal misalignments that overall result in mitotic stress and a high DNA content. Such mitotic block prompts premature keratinocyte differentiation in a p53-dependent manner in the absence of cell death. Our findings reveal a novel role for Clasp2 in governing keratinocyte undifferentiated features and highlight the presence of surveillance mechanisms that avoid cell cycle entry in cells with alterations in the DNA content.


Perez-Moreno M.,Epithelial Cell Biology Group | Fuchs E.,Howard Hughes Medical Institute
Journal of Cell Biology | Year: 2012

Members of the p120-catenin family associate with cadherins and regulate their stability at the plasma membrane. How p120-catenin limits cadherin endocytosis has long remained a mystery. In this issue, Nanes et al. (2012. J. Cell Biol. doi:10.1083/jcb.201205029) identify a conserved acidic motif within cadherins that acts as a physical platform for p120-catenin binding. However, in the absence of p120-catenin, the motif acts as an endocytic signal. These results provide new insight into p120-catenin's role as guardian of intercellular junction dynamics. © 2012 Perez-Moreno and Fuchs.


Shahbazi M.N.,University of Cambridge | Perez-Moreno M.,Epithelial Cell Biology Group
Tissue Barriers | Year: 2015

Cadherin-catenin mediated adhesion is an important determinant of tissue architecture in multicellular organisms. Cancer progression and maintenance is frequently associated with loss of their expression or functional activity, which not only leads to decreased cell-cell adhesion, but also to enhanced tumor cell proliferation and loss of differentiated characteristics. This review is focused on the emerging implications of cadherin-catenin proteins in the regulation of polarized divisions through their connections with the centrosomes, cytoskeleton, tissue tension and signaling pathways; and illustrates how alterations in cadherin-catenin levels or functional activity may render cells susceptible to transformation through the loss of their proliferation-differentiation balance. © 2015, © Taylor & Francis Group, LLC.


Epifano C.,Epithelial Cell Biology Group | Perez-Moreno M.,Epithelial Cell Biology Group
Cell Adhesion and Migration | Year: 2012

Adhesion events mediated by cadherin and integrin adhesion receptors have fundamental roles in the maintenance of the physiological balance of epithelial tissues, and it is well established that perturbations in their normal functional activity and/or changes in their expression are associated with tumorigenesis. Over the last decades, increasing evidence of a dynamic collaborative interaction between these complexes through their shared interactions with cytoskeletal proteins and common signaling pathways has emerged not only as an important regulator of several aspects of epithelial cell behavior, but also as a coordinated adhesion module that senses and transmits signals from and to the epithelia surrounding microenvironment. The tight regulation of their crosstalk is particularly important during epithelial remodeling events that normally take place during morphogenesis and tissue repair, and when defective it leads to cell transformation and aggravated responses of the tumor microenvironment that contribute to tumorigenesis. In this review we highlight some of the interactions that regulate their crosstalk and how this could be implicated in regulating signals across epithelial tissues to sustain homeostasis. © 2012 Landes Bioscience.


PubMed | Epithelial Cell Biology Group and University of Cambridge
Type: Journal Article | Journal: Tissue barriers | Year: 2015

Cadherin-catenin mediated adhesion is an important determinant of tissue architecture in multicellular organisms. Cancer progression and maintenance is frequently associated with loss of their expression or functional activity, which not only leads to decreased cell-cell adhesion, but also to enhanced tumor cell proliferation and loss of differentiated characteristics. This review is focused on the emerging implications of cadherin-catenin proteins in the regulation of polarized divisions through their connections with the centrosomes, cytoskeleton, tissue tension and signaling pathways; and illustrates how alterations in cadherin-catenin levels or functional activity may render cells susceptible to transformation through the loss of their proliferation-differentiation balance.

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