RENEWING SKIN MINDS

It is unclear how the skin maintains the balance between cell multiplication and shedding in hyperplastic lesions. For instance, how does the skin maintain squamous differentiation in hyperproliferative psoriasis ? 

This question minds very much to the skin and to skin cancer. To answer it, we may need changing minds.

We defend and discuss a new Model for cell cycle-driven epidermal homeostasis maintenance in a View Point at Experimental Dermatology, formated final PDF in
http://onlinelibrary.wiley.com/doi/10.1111/exd.12287/pdf

Cycling up the epidermis. Cycling may help keratinocytes climb up through the suprabasal layers.
Figure 2b. Gandarillas & Freije, Experimental Dermatology, doi/10.1111/exd.12287

NEW WORK IN EXPERIMENTAL DERMATOLOGY

-OPEN ACCESS-

Cycling up the epidermis: reconciling 100 years of debate.

 Alberto Gandarillas^1,2,* and Ana Freije¹

Experimental Dermatology.
Unformated preview in
http://onlinelibrary.wiley.com/doi/10.1111/exd.12287/abstract

ABSTRACT

There is likely general consensus within the skin research community that cell cycle control is critical to epidermal homeostasis and disease. The current predominant model proposes that keratinocytes switch off DNA replication and undergo cell cycle and cell growth arrest as they initiate terminal differentiation. However, this model cannot explain key physiological features of the skin, mainly why squamous differentiation prevails over proliferation in benign hyperproliferative disorders. In recent years we have proposed an alternative model that involves mitotic slippage and endoreplication. This new model is controversial and has encountered resistance within the field. However, looking back at history, the epidermal cell cycle has been a matter of controversy and debate for around 100 years now. The accumulated data are confusing and contradictory. Our present model can explain and reconcile both old and new paradoxical observations. Here we explain and discuss the endoreplicative cell cycle, the evidence for and against its existence in human epidermis and the important implications for skin homeostasis and disease. We show that regardless of the strengths or weaknesses of the Endoreplication Model, the existing evidence in support of the Cell Cycle Arrest Model is very weak.

Keywords: DNA damage – MYC - endocycles – cancer –carcinoma

This article is protected by copyright. All rigths reserved

NEW WORK IN MOLECULAR CANCER

We collaborate with Marisa Martín-Faraldo and Marina Glukhova on the role of MYC in the mammary gland (Moumen et al, 2012; Moumen et al, 2013).

Mol Cancer. 2013 Oct 30;12(1):132. [Epub ahead of print]

WHOLE TEXT IN http://www.molecular-cancer.com/content/12/1/132

Myc is required for beta-catenin-mediated mammary stem cell amplification and tumorigenesis.

Moumen M, Chiche A, Decraene C, Petit V, Gandarillas A, Deugnier MA, Glukhova MA, Faraldo MM.

Abstract

BACKGROUND:

Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 overexpression. Recent studies have linked activation of the Wnt/beta-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5DeltaNbetacat previously generated by our team present a constitutive activation of Wnt/beta-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5DeltaNbetacat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers.

METHODS:

Microarray analysis was used to compare K5DeltaNbetacat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5DeltaNbetacat mice. Stem cell amplification in K5DeltaNbetacat mouse mammary epithelium was assessed with 3D-culture and transplantation assays.

RESULTS:

Histological and microarray analyses of the mammary lesions of K5DeltaNbetacat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5DeltaNbetacat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5DeltaNbetacat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5DeltaNbetacat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis.

CONCLUSIONS:

These results strongly indicate that beta-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.

PMID: 24171719 [PubMed - as supplied by publisher] Free full text

 

POSITIONS AVAILABLE / VACANTES

We have positions available for a Master/PhD student and a Postdoctoral fellow.

Send CV and a presentation letter to: agandarillaslab@gmail.com

PROYECTO INTERNACIONAL EN BUSCA DE ESTUDIANTES DE MÁSTER  DOCTORADO Y POSTDOCTORALES COMPETITIVOS Y MOTIVADOS PARA LA INVESTIGACIÓN

Enviar CV y carta de motivación a: agandarillaslab@gmail.com


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CURSO 'NUEVAS TECNOLOGIAS EN LA SALUD DE LA PIEL' -SPANISH-

El curso de verano que organizamos junto con el Profesor de la UC José Luis Arce Diego en Septiembre fue un éxito a decir de alumnos y por la calidad y diversidad de las ponencias de los profesores. También tuvo acogida en los medios de comunicación.
El énfasis del Curso estuvo en la importancia de la prevención y la concienciación antes que nada. Además se impartieron contenidos multidisciplinarios con el objetivo común de la Piel.

Aquí colgamos artículos en la prensa, fotos y el vínculo a un vídeo de TVE.
Esperamos repetir el año que viene.

Gracias a la Universidad de Cantabria-UC, a los patrocinadores:
ABBVIE FARMACÉUTICA SLU, INDUSTRIAL FARMACÉUTICA CANTABRIA (IFC)
CARL ZEISS MICROSCOPY/GRUPO TAPER, CLÍNICA SANZ, 
BETSON DICKINSON BIOCIENCIAS, FISHER SCIENTIFIC,
INNOVA INFORMÁTICA, ASOCIACIÓN ESPAÑOLA CONTRA EL CANCER (AECC)
HOSPITAL MARQUÉS DE VALDECILLA (HUMV)
AYUNTAMIENTO DE SANTANDER

Gracias al Rector de la Universidad y a la presidenta de la Asociación Contra el Cáncer (AEC) de Cantabria, por asistir a la Inauguración, y al Director Técnico de Desarrollo y Calidad del Sistema Cántabro de Salud, que participó en el acto de clausura.

Y sobre todo gracias a los alumnos del curso por su asistencia y su interés.
min.8:28: http://www.rtve.es/alacarta/videos/telecantabria/telecantabria-11-09-13/2016850/




Inauguración por el Rector, Presidenta de AEC y Directores del Curso



Directores del Curso con representantes de la Industria

La Dra Ana Freije explica la biología molecular del cáncer epitelial de piel



Tomando notas

Ponencia del Dr JR Sanz

Los Alumnos



Clausura por el Director Técnico del SCS y los Directores del Curso



NEW WORK IN JOURNAL OF DERMATOLOGICAL SCIENCE

We collaborate with Agusti Toll and Ramón Pujol of the Hospital del Mar/IMIM to investigate the mechanisms leading to agressiveness of skin carcinomas.

J Dermatol Sci. 2013 Jul 15. pii: S0923-1811(13)00245-4. doi: 10.1016/j.jdermsci.2013.07.001. [Epub ahead of print]

Epithelial to mesenchymal transition markers are associated with an increased metastatic risk in primary cutaneous squamous cell carcinomas but are attenuated in lymph node metastases.

Toll A, Masferrer E, Hernández-Ruiz ME, Ferrandiz-Pulido C, Yébenes M, Jaka A, Tuneu A, Jucglà A, Gimeno J, Baró T, Casado B, Gandarillas A, Costa I, Mojal S, Peña R, de Herreros AG, García-Patos V, Pujol RM, Hernández-Muñoz I.

Servei de Dermatologia, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain; Cancer Research Program, IMIM (Institut Hospital del Mar d'Investigacions Mèdiques), Barcelona, Spain.
Abstract
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy in humans and approximately 5% metastasize, usually to regional lymph nodes. Epithelial to mesenchymal transition (EMT) is a process involving loss of intercellular adhesion, acquisition of a mesenchymal phenotype and enhanced migratory potential; epithelial markers, such as E-cadherin, are down-regulated and mesenchymal proteins (Vimentin), increased.
OBJECTIVE: To investigate the expression of EMT markers in metastatic SCC (MSCC) and their corresponding metastases, and to correlate them with clinico-pathological factors associated with an increased risk of metastasis.
METHODS: We performed a retrospective study that included 146 cSCC samples (51 primary non-metastatic, 56 primary metastatic, 39 lymphatic metastases). Immunohistochemistry for E-cadherin, Vimentin, Snail, beta-catenin, Twist, Zeb1 and Podoplanin was performed.
RESULTS: Loss of membranous E-cadherin was observed in 77% cSCCs, with no differences between MSCC and non-MSCC. Among the transcriptional factors controlling EMT, no significant Snail1 expression was detected. Twist, Zeb1, Vimentin, beta-catenin and Podoplanin were significantly overexpressed in MSCCs. Twist ectopic expression in SCC13 cells induced Zeb1, Vimentin and Podoplanin expression and E-cadherin delocalization. These changes resulted in a scattered migration pattern in vitro. Expression of EMT markers was decreased in the metastases when compared with the corresponding primary tumors.
CONCLUSION: These results suggest that a partial EMT, characterized by the expression of Twist but without a total E-cadherin depletion, is involved in the acquisition of invasive traits by cSCC, but the process is downregulated in lymph node metastases.

KEYWORDS: Cutaneous squamous cell carcinoma, E-cadherin, Epithelial to mesenchymal transition, Metastasis, Twist, Vimentin
Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

WE ORGANISE A MULTIDISCIPLINARY UNIVERSITY SUMMER COURSE ON THE SKIN -SPANISH-

NUEVAS TECNOLOGÍAS EN SALUD DE LA PIEL

11-13 SEPTIEMBRE, 2013
http://cursosdeverano.unican.es/Cursos/Paginas/Detalle-curso.aspx?p_id=2097

　
La piel es un problema creciente en salud pública debido a su carácter multifactorial, a su exposición al medio ambiente, y a las tendencias estéticas imperantes. El cáncer de piel es el más frecuente y ha aumentado en un 20% en las últimas décadas, especialmente en mujeres jóvenes. Sin embargo el cáncer es solo una de las muchas patologías que impactan en la calidad de vida a través de la piel, y que comprenden alteraciones inflamatorias como la psoriasis, hiperplásicas como las queratosis y las dermatitis, o degenerativas como el envejecimiento y la alopecia. Los tratamientos de estos problemas en dermatología están viviendo una evolución tecnológica importante gracias a avances en ingeniería, física y biología celular y molecular.
El curso trata la salud de la piel desde este ángulo multidisciplinar, aprovechando la diversidad de conocimiento de la UC y el Hospital de Valdecilla, y abordando temas de mucha actualidad. Se estructura de esta manera: I- Introducción a las patologías de la piel, técnicas actuales de tratamiento y diagnóstico. II- Nuevas estrategias terapéuticas emergentes desde la bioingeniería, óptica biomédica, nanotecnología, células madre y terapia génica. III- Presente y futuro del sector de la industria farmacológica, dermatológica y estética. IV- Cooperación y prevención para la salud de la piel.
El curso está dirigido a estudiantes y profesionales del ámbito público y privado de las especialidades tratadas, con el objetivo de aumentar su conocimiento y capacitación profesional en esta temática de creciente demanda social y laboral.

 

CTCFL/BORIS AND MITOSIS

Epigenetic factor CTCFL/BORIS localises to nucleoli and centrosomes of human primary epidermal keratinocytes.

BORIS accumulates in keratinocytes upon mitosis failure. It might therefore be involved in genomic instability by participating in the coordination between S phase (DNA replication, centrosome duplication) and Mitosis (DNA replication and RNA transcription arrest and chromosome condensation).

Human epidermal keratinocytes treated with an AURORA B KINASE inhibitor that blocks mitosis.
Green is centrosome marker gamma-tubulin, red is BORIS, blue is Dapi for the chromosomal DNA.
Note the abnormal metaphase figures or nuclei caused by AURB inhibition.

See also Rosa-Garrido et al, PLoS ONE 2012, 7(6): e39371. doi:10.1371/journal.pone.0039371.

INHIBITING THE KERATINOCYTE CELL CYCLE KINASES

• 48h inhibiting mitotic kinases in human skin keratinocytes irreversibly induces terminal differentiation and suppresses clonogenic potential. However,
• 48h inhibiting cell cycle entry kinase cdk2 delays differentiation and confers a higher clonogenic potential.

Further suggesting that epidermal keratinocytes need cell growth to fully differentiate.




 
Colonies of human primary keratinocytes after the treatments indicated.

Double immunofluorescence for Cyclin E (red) and the differentiation

marker involucrin (green), DNA was stained in blue by DAPI  (Upper Panels).

Note that inhibition of mitotic kinases (cdk1, Pololk) renders small, differentiated colonies,

whose cells irreversibly lose their capacity to proliferate.

Bar:100 µm. Freije et al, Oncogene, 2012, Supplementary Data.

   

EPIDERMAL STARS

We investigate the cell cycle and differentiation of skin epidermal cells. Both need to be coordinated as an orchestra to avoid neoplasic development.
In vitro, we study the links governing epidermal homeostasis that protect the skin from cancer.

Primary keratinocytes behave closely resembling the physiology of the skin.
In situ, we study skin cancer.

Our research walks on the edge between molecular developmental cues and human disease.

Primary human keratinocytes expresing a GFP form of a cell cycle regulator (GREEN) and a differentiation keratin (RED).
Skin from the Peadriatic Surgery Department of Valdecilla hospital in Santander.
Cell culture and staining by Laura Ceballos.

  

A SKIN COVER FOR 'CELL CYCLE'

A molecular switch triggers squamous differentiation and endoreplication upon cell cycle hyperactivation.






Gandarillas, Dic. 2012 -COVER- http://www.landesbioscience.com/journals/cc/



WE COVER THE CELL CYCLE

Cell Cycle journal has selected one of our images for the current December 2012 issue cover.
http://www.landesbioscience.com/journals/cc/



Deregulation of the keratinocyte cell cycle induces epidermal differentiation. Human
epidermal keratinocytes overexpressing fluorescent cyclin E (green) and the differentiation marker involucrin (red).
For more information, Gandarillas., pp. 4507–16.
See also Freije et al, 2012, http://www.nature.com/onc/journal/v31/n50/abs/onc201222a.html

 

PROYECTO EUROPEO EN ALERTA (Spanish)-

THE NEW SKIN EPIDERMAL CELL CYCLE IN CELL CYCLE -open access


Cell Cycle. 2012 Oct 31;11(24). [Epub ahead of print]
http://www.landesbioscience.com/journals/cc/article/22529/

Source http://www.ncbi.nlm.nih.gov/pubmed/23114621

The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint.

Gandarillas A.

Cell Cycle, Stem Cell Fate and Cancer Laboratory; Fundación Marqués de Valdecilla-Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV); Santander, Spain; Institut National de la Santé et de la Recherche Médicale (INSERM); ADR Languedoc-Roussillon; Montpellier, France.

Abstract

  


Gandarillas, 2012, Cell Cycle

Fifteen years ago, we reported that proto-oncogene MYC promoted differentiation of human epidermal stem cells, a finding that was surprising to the MYC and the skin research communities. MYC was one of the first human oncogenes identified, and it had been strongly associated with proliferation. However, it was later shown that MYC could induce apoptosis under low survival conditions. Currently, the notion that MYC promotes epidermal differentiation is widely accepted, but the cell cycle mechanisms that elicit this function remain unresolved. We have recently reported that keratinocytes respond to cell cycle deregulation and DNA damage by triggering terminal differentiation. This mechanism might constitute a homeostatic protection face to cell cycle insults. Here, I discuss recent and not-so-recent evidence suggesting the existence of a largely unexplored oncogene-induced differentiation response (OID) analogous to oncogene-induced apoptosis (OIA) or senescence (OIS). In addition, I propose a model for the role of the cell cycle in skin homeostasis maintenance and for the dual role of MYC in differentiation.

PMID:

23114621

[PubMed - as supplied by publisher]