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Cédric Blanpain

Adriana Sánchez-Danés, Edouard Hannezo, Jean-Christophe Larsimont, Mélanie Liagre, Khalil Kass Youssef, Benjamin D Simons, Cédric Blanpain
The changes in cell dynamics after oncogenic mutation that lead to the development of tumours are currently unknown. Here, using skin epidermis as a model, we assessed the effect of oncogenic hedgehog signalling in distinct cell populations and their capacity to induce basal cell carcinoma, the most frequent cancer in humans. We found that only stem cells, and not progenitors, initiated tumour formation upon oncogenic hedgehog signalling. This difference was due to the hierarchical organization of tumour growth in oncogene-targeted stem cells, characterized by an increase in symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours...
August 18, 2016: Nature
Carmen Adriaens, Laura Standaert, Jasmine Barra, Mathilde Latil, Annelien Verfaillie, Peter Kalev, Bram Boeckx, Paul W G Wijnhoven, Enrico Radaelli, William Vermi, Eleonora Leucci, Gaëlle Lapouge, Benjamin Beck, Joost van den Oord, Shinichi Nakagawa, Tetsuro Hirose, Anna A Sablina, Diether Lambrechts, Stein Aerts, Cédric Blanpain, Jean-Christophe Marine
In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis...
August 2016: Nature Medicine
Aline Wuidart, Marielle Ousset, Steffen Rulands, Benjamin D Simons, Alexandra Van Keymeulen, Cédric Blanpain
Lineage tracing has become the method of choice to study the fate and dynamics of stem cells (SCs) during development, homeostasis, and regeneration. However, transgenic and knock-in Cre drivers used to perform lineage tracing experiments are often dynamically, temporally, and heterogeneously expressed, leading to the initial labeling of different cell types and thereby complicating their interpretation. Here, we developed two methods: the first one based on statistical analysis of multicolor lineage tracing, allowing the definition of multipotency potential to be achieved with high confidence, and the second one based on lineage tracing at saturation to assess the fate of all SCs within a given lineage and the "flux" of cells between different lineages...
June 1, 2016: Genes & Development
Dany Nassar, Cédric Blanpain
Different mechanisms contribute to intratumor heterogeneity, including genetic mutations, the microenvironment, and the existence of subpopulations of cancer cells with increased renewal capacity and the ability to recapitulate the heterogeneity found in primary tumors, which are referred to as cancer stem cells (CSCs). In this review, we discuss how the concept of CSCs has been defined, what assays are currently used to define the functional properties of CSCs, what intrinsic and extrinsic mechanisms regulate CSC functions, how plastic CSCs are, and the importance of epithelial-to-mesenchymal transition in conferring CSC properties...
May 23, 2016: Annual Review of Pathology
Giuseppe Chiapparo, Xionghui Lin, Fabienne Lescroart, Samira Chabab, Catherine Paulissen, Lorenzo Pitisci, Antoine Bondue, Cédric Blanpain
During embryonic development, Mesp1 marks the earliest cardiovascular progenitors (CPs) and promotes their specification, epithelial-mesenchymal transition (EMT), and cardiovascular differentiation. However, Mesp1 deletion in mice does not impair initial CP specification and early cardiac differentiation but induces cardiac malformations thought to arise from a defect of CP migration. Using inducible gain-of-function experiments during embryonic stem cell differentiation, we found that Mesp2, its closest homolog, was as efficient as Mesp1 at promoting CP specification, EMT, and cardiovascular differentiation...
May 23, 2016: Journal of Cell Biology
Dany Nassar, Mathilde Latil, Bram Boeckx, Diether Lambrechts, Cédric Blanpain
No abstract text is available yet for this article.
February 2016: Nature Medicine
Soufiane Boumahdi, Cédric Blanpain
No abstract text is available yet for this article.
January 29, 2016: Science
Samira Chabab, Fabienne Lescroart, Steffen Rulands, Navrita Mathiah, Benjamin D Simons, Cédric Blanpain
The heart arises from distinct sources of cardiac progenitors that independently express Mesp1 during gastrulation. The precise number of Mesp1 progenitors that are specified during the early stage of gastrulation, and their clonal behavior during heart morphogenesis, is currently unknown. Here, we used clonal and mosaic tracing of Mesp1-expressing cells combined with quantitative biophysical analysis of the clonal data to define the number of cardiac progenitors and their mode of growth during heart development...
January 5, 2016: Cell Reports
Sabela Búa, Peggy Sotiropoulou, Cecilia Sgarlata, Luis R Borlado, Manuel Eguren, Orlando Domínguez, Sagrario Ortega, Marcos Malumbres, Cedric Blanpain, Juan Méndez
Cdc6 encodes a key protein for DNA replication, responsible for the recruitment of the MCM helicase to replication origins during the G1 phase of the cell division cycle. The oncogenic potential of deregulated Cdc6 expression has been inferred from cellular studies, but no mouse models have been described to study its effects in mammalian tissues. Here we report the generation of K5-Cdc6, a transgenic mouse strain in which Cdc6 expression is deregulated in tissues with stratified epithelia. Higher levels of CDC6 protein enhanced the loading of MCM complexes to DNA in epidermal keratinocytes, without affecting their proliferation rate or inducing DNA damage...
2015: Cell Cycle
Özdemirhan Serçin, Jean-Christophe Larsimont, Andrea E Karambelas, Veronique Marthiens, Virginie Moers, Bram Boeckx, Marie Le Mercier, Diether Lambrechts, Renata Basto, Cédric Blanpain
Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects...
January 2016: Nature Cell Biology
Alexandra Van Keymeulen, May Yin Lee, Marielle Ousset, Sylvain Brohée, Sandrine Rorive, Rajshekhar R Giraddi, Aline Wuidart, Gaëlle Bouvencourt, Christine Dubois, Isabelle Salmon, Christos Sotiriou, Wayne A Phillips, Cédric Blanpain
Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity...
September 3, 2015: Nature
Ash A Alizadeh, Victoria Aranda, Alberto Bardelli, Cedric Blanpain, Christoph Bock, Christine Borowski, Carlos Caldas, Andrea Califano, Michael Doherty, Markus Elsner, Manel Esteller, Rebecca Fitzgerald, Jan O Korbel, Peter Lichter, Christopher E Mason, Nicholas Navin, Dana Pe'er, Kornelia Polyak, Charles W M Roberts, Lillian Siu, Alexandra Snyder, Hannah Stower, Charles Swanton, Roel G W Verhaak, Jean C Zenklusen, Johannes Zuber, Jessica Zucman-Rossi
The extent of tumor heterogeneity is an emerging theme that researchers are only beginning to understand. How genetic and epigenetic heterogeneity affects tumor evolution and clinical progression is unknown. The precise nature of the environmental factors that influence this heterogeneity is also yet to be characterized. Nature Medicine, Nature Biotechnology and the Volkswagen Foundation organized a meeting focused on identifying the obstacles that need to be overcome to advance translational research in and tumor heterogeneity...
August 2015: Nature Medicine
Dany Nassar, Mathilde Latil, Bram Boeckx, Diether Lambrechts, Cédric Blanpain
Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53...
August 2015: Nature Medicine
Romaric Bouveret, Ashley J Waardenberg, Nicole Schonrock, Mirana Ramialison, Tram Doan, Danielle de Jong, Antoine Bondue, Gurpreet Kaur, Stephanie Mohamed, Hananeh Fonoudi, Chiann-Mun Chen, Merridee A Wouters, Shoumo Bhattacharya, Nicolas Plachta, Sally L Dunwoodie, Gavin Chapman, Cédric Blanpain, Richard P Harvey
We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD)...
2015: ELife
Julie K Watson, Steffen Rulands, Adam C Wilkinson, Aline Wuidart, Marielle Ousset, Alexandra Van Keymeulen, Berthold Göttgens, Cédric Blanpain, Benjamin D Simons, Emma L Rawlins
Epithelial lineages have been studied at cellular resolution in multiple organs that turn over rapidly. However, many epithelia, including those of the lung, liver, pancreas, and prostate, turn over slowly and may be regulated differently. We investigated the mouse tracheal epithelial lineage at homeostasis by using long-term clonal analysis and mathematical modeling. This pseudostratified epithelium contains basal cells and secretory and multiciliated luminal cells. Our analysis revealed that basal cells are heterogeneous, comprising approximately equal numbers of multipotent stem cells and committed precursors, which persist in the basal layer for 11 days before differentiating to luminal fate...
July 7, 2015: Cell Reports
Jean-Christophe Larsimont, Khalil Kass Youssef, Adriana Sánchez-Danés, Vijayakumar Sukumaran, Matthieu Defrance, Benjamin Delatte, Mélanie Liagre, Pieter Baatsen, Jean-Christophe Marine, Saskia Lippens, Christopher Guerin, Véronique Del Marmol, Jean-Marie Vanderwinden, Francois Fuks, Cédric Blanpain
Sox9 is a transcription factor expressed in most solid tumors. However, the molecular mechanisms underlying Sox9 function during tumorigenesis remain unclear. Here, using a genetic mouse model of basal cell carcinoma (BCC), the most frequent cancer in humans, we show that Sox9 is expressed from the earliest step of tumor formation in a Wnt/β-catenin-dependent manner. Deletion of Sox9 together with the constitutive activation of Hedgehog signaling completely prevents BCC formation and leads to a progressive loss of oncogene-expressing cells...
July 2, 2015: Cell Stem Cell
Jean-Christophe Larsimont, Cédric Blanpain
Stem cell gene therapy followed by transplantation into damaged regions of the skin has been successfully used to treat genetic skin blistering disorder. Usually, many stem cells are virally transduced to obtain a sufficient number of genetically corrected cells required for successful transplantation, as genetic insertion in every stem cell cannot be precisely defined. In this issue of EMBO Molecular Medicine, Droz-Georget Lathion et al developed a new strategy for ex vivo single cell gene therapy that allows extensive genomic and functional characterization of the genetically repaired individual cells before they can be used in clinical settings...
April 2015: EMBO Molecular Medicine
Sigolène M Meilhac, Fabienne Lescroart, Cédric Blanpain, Margaret E Buckingham
No abstract text is available yet for this article.
February 2015: Cold Spring Harbor Perspectives in Medicine
Benjamin Beck, Gaëlle Lapouge, Sandrine Rorive, Benjamin Drogat, Kylie Desaedelaere, Stephanie Delafaille, Christine Dubois, Isabelle Salmon, Karen Willekens, Jean-Christophe Marine, Cédric Blanpain
Twist1 promotes epithelial-to-mesenchymal transition (EMT), invasion, metastasis, and cancer stem cell (CSC) properties. However, it remains unclear whether Twist1 is also required for tumor initiation and whether Twist1-induced cancer stemness and EMT are functionally linked. Using a conditional deletion of Twist1 at different stages of skin carcinogenesis, we show that Twist1 is required for skin tumor initiation and progression in a gene-dosage-dependent manner. Moreover, conditional ablation of Twist1 in benign tumors leads to increased apoptosis, reduced cell proliferation, and defective tumor maintenance and propagation independently of its EMT-inducing abilities...
January 8, 2015: Cell Stem Cell
Sigolène M Meilhac, Fabienne Lescroart, Cédric Blanpain, Margaret E Buckingham
Myocardial cells ensure the contractility of the heart, which also depends on other mesodermal cell types for its function. Embryological experiments had identified the sources of cardiac precursor cells. With the advent of genetic engineering, novel tools have been used to reconstruct the lineage tree of cardiac cells that contribute to different parts of the heart, map the development of cardiac regions, and characterize their genetic signature. Such knowledge is of fundamental importance for our understanding of cardiogenesis and also for the diagnosis and treatment of heart malformations...
September 2014: Cold Spring Harbor Perspectives in Medicine
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