NEW WORK IN ONCOGENE

 
Online ahead of print.

p21CIP1 controls the squamous differentiation response to replication stress

Isabel de Pedro  ¹ , Jesús Galán-Vidal  ¹ , Ana Freije  ¹ , Ernesto de Diego  ^{1   2} , Alberto Gandarillas  ^{3   4}

Affiliations

• PMID: 33097856
• DOI: 10.1038/s41388-020-01520-8

Abstract

The control of cell fate is critical to homeostasis and cancer. Cell cycle cdk inhibitor p21CIP1 has a central and paradoxical role in the regulatory crossroads leading to senescence, apoptosis, or differentiation. p21 is an essential target of tumor suppressor p53, but it also is regulated independently. In squamous self-renewal epithelia continuously exposed to mutagenesis, p21 controls cell fate by mechanisms still intriguing. We previously identified a novel epidermoid DNA damage-differentiation response. We here show that p21 intervenes in the mitosis block that is required for the squamous differentiation response to cell cycle deregulation and replication stress. The inactivation of endogenous p21 in human primary keratinocytes alleviated the differentiation response to oncogenic loss of p53 or overexpression of the DNA replication major regulator Cyclin E. The bypass of p21-induced mitotic block involving upregulation of Cyclin B allowed DNA damaged cells to escape differentiation and continue to proliferate. In addition, loss of p21 drove keratinocytes from differentiation to apoptosis upon moderate UV irradiation. The results show that p21 is required to drive keratinocytes towards differentiation in response to genomic stress and shed light into its dual and paradoxical role in carcinogenesis. 

 

 

 

LETTER IN NATURE: COVID SHOWS THAT SCIENCE FUNDING COULD BE SIMPLER AND FASTER

(CARTA EN NATURE: COVID MUESTRA QUE LA FINANCIACIÓN DE LA CIENCIA PUEDE SER MUCHO MÁS SENCILLA Y MÁS RÁPIDA)

 

CORRESPONDENCE

28 July 2020

UK funders learn from COVID-19 ‘white-water ride’

Louise Wood & Fiona M. Watt

The UK government’s aim to reduce bureaucracy in science funding — by cutting out ‘unnecessary paperwork, arduous funding applications and research selection processes’ (see go.nature.com/3fbxirc) — has received an unexpected boost from the COVID-19 pandemic.

The UK National Institute for Health Research (NIHR) and Medical Research Council (MRC) typically take about six to eight months to reach a decision on a grant application, and would normally ask applicants to make separate submissions to each funder. In response to the pandemic, however, the NIHR and MRC have been running calls that incorporate a single, streamlined application process with independent peer review and a turnaround time of three to four weeks. This has enabled us to co-fund two vaccines that are now being tested in human volunteers and to disburse funds rapidly for drug repurposing (such as the RECOVERY trial; www.recoverytrial.net).

Our COVID-19 funding activity has felt like a white-water ride as we focus on realizing patient benefit on an aggressive timescale of 12 months. Although the pace of decision-making need not always be so fast, we now know that we can speed it up without any detriment to the quality of those decisions. Our appetite for adventure has been whetted.

Nature 583, 683 (2020)

doi: https://doi.org/10.1038/d41586-020-02236-1

 

NEW WORK IN JOURNAL OF CELL BIOLOGY

 

Article | October 01 2020

The DDR signals control epidermoid differentiation

Rut Molinuevo, Ana Freije, Lizbeth Contreras, Juan R. Sanz, Alberto Gandarillas

Molinuevo et al. show a novel control of epidermoid differentiation by the DNA damage response signals and propose a model for automatic cleansing of stratified self-renewal epithelia facing genotoxic agents.

 

doi: 10.1083/jcb.202001063.

The DNA damage response links human squamous proliferation with differentiation

Rut Molinuevo  ¹ , Ana Freije  ¹ , Lizbeth Contreras  ¹ , Juan R Sanz  ^{1   2   3} , Alberto Gandarillas  ^{1   4}

Affiliations

• PMID: 33007086
• DOI: 10.1083/jcb.202001063

Abstract

 

How rapid cell multiplication leads to cell differentiation in developing tissues is still enigmatic. This question is central to morphogenesis, cell number control, and homeostasis. Self-renewal epidermoid epithelia are continuously exposed to mutagens and are the most common target of cancer. Unknown mechanisms commit rapidly proliferating cells to post-mitotic terminal differentiation. We have over-activated or inhibited the endogenous DNA damage response (DDR) pathways by combinations of activating TopBP1 protein, specific shRNAs, or chemical inhibitors for ATR, ATM, and/or DNA-PK. The results dissect and demonstrate that these signals control keratinocyte differentiation in proliferating cells independently of actual DNA damage. The DDR limits keratinocyte multiplication upon hyperproliferative stimuli. Moreover, knocking down H2AX, a common target of the DDR pathways, inhibits the epidermoid phenotype. The results altogether show that the DDR is required to maintain the balance proliferation differentiation and suggest that is part of the squamous program. We propose a homeostatic model where genetic damage is automatically and continuously cleansed by cell-autonomous mechanisms.  

NUESTRA ÚLTIMA PUBLICACIÓN EN LA PRENSA

Nota de prensa del Sistema Cántabro de Salud

https://www.scsalud.es/web/scs/detalle/-/journal_content/56_INSTANCE_DETALLE/16413/9064112

Este estudio tiene directa aplicación en el cáncer epidermoide al aportar nuevas vías de pronóstico y de terapia


Santander - 29.02.2020

El equipo de investigación Ciclo Celular, Células Madre y Cáncer de la Fundación Instituto de Investigación Sanitaria Valdecilla (IDIVAL), liderado por el doctor Alberto Gandarillas, acaba de publicar un trabajo que recoge la regulación molecular que hace posible que las células de epitelios como la epidermis de la piel no mueran frente a agentes carcinógenos continuos como la luz del sol.
Este descubrimiento ha permitido identificar un gen que permite a la piel funcionar a pesar de estar expuesta de forma cotidiana al sol sin que sus células mueran por apoptosis.
El doctor Gandarillas ha indicado que los resultados de este estudio tienen directa aplicación en el cáncer epidermoide, ya que aportan nuevas vías de pronóstico y de terapia. Este tipo de cáncer, que causa unas 12.000 muertes al año en España, es la segunda neoplasia más frecuente y una de las principales causas de muerte por cáncer, que surge en una variedad de tejidos como la piel, boca, garganta, esófago o pulmón y que, por lo general, suele ser agresivo y de mal tratamiento.
Según ha explicado Alberto Gandarillas, la exposición continua de las células de la epidermis a la radiación solar provoca un daño en el ADN, a pesar de que externamente no se manifieste por una quemadura o enrojecimiento de la piel.
La respuesta conocida de las células al daño genético, ha señalado, es la apoptosis o muerte celular programada. Como ejemplo de este fenómeno, "que se utiliza mucho en terapias antitumorales", ha citado el hecho de que siempre se ha asumido que la radioterapia elimina células tumorales por apoptosis.
Sin embargo, en el caso de la epidermis las células no mueren por apoptosis en respuesta a los efectos cotidianos del sol, ya que "si fuera así no tendríamos piel", ha precisado.
El doctor Gandarillas ha destacado que ya tenían respuesta al fenómeno del pelado de la piel por efecto de la luz ultravioleta, "que no se da necesariamente por muerte celular, por necrosis o quemadura, sino por una acumulación del daño genético". También conocíamos que esta respuesta se da en células de la boca y la garganta, que también están continuamente expuesta a carcinógenos como el tabaco y el alcohol.
"Pero seguíamos sin entender", ha apuntado, "cómo o por qué las células de estos epitelios escapan de la apoptosis y consiguen mantener el tejido a pesar del impacto continuo en su ADN".
En este sentido, ha indicado que el trabajo de investigación ha permitido demostrar que moléculas que controlan la división celular protegen a las células epiteliales de la piel, la boca y el cuello de la muerte celular frente al daño genético continuado. "Al eliminar el gen CDC20 las células de la piel morían". Genes como este permiten la existencia de estos tejidos, su renovación y su función a pesar de estar expuestos a mutágenos de forma crónica, ha concluido.
El trabajo, publicado en la revista 'Cell Death and Differentiation', del Grupo Nature, ha sido realizado en colaboración con los grupos de investigación del Centro Nacional de Investigaciones Oncológicas (CNIO) liderados por Mariano Barbacid y Marcos Malumbres.

La Vanguardia 
https://www.lavanguardia.com/local/cantabria/20200229/473838701181/investigadores-del-idival-realizan-un-descubrimiento-que-contribuira-a-luchar-contra-el-cancer.html

Eldiario.es
https://www.eldiario.es/cantabria/ultima-hora/Investigadores-IDIVAL-realizan-descubrimiento-contribuira_0_1000900052.html

NEW WORK IN CELL DEATH AND DIFFFERENTIATION -OPEN ACCESS

Within this manuscript we show new in vivo insight into the control of cell fate by mitotic checkpoints in response to cell cycle stress. 
 
https://www.nature.com/articles/s41418-020-0515-2


Cell Death Differ. 2020 Feb 20. doi: 10.1038/s41418-020-0515-2. [Epub ahead of print]

Squamous differentiation requires G2/mitosis slippage to avoid apoptosis.

Sanz-Gómez N¹, de Pedro I¹, Ortigosa B², Santamaría D^3,4, Malumbres M⁵, de Cárcer G^2,5, Gandarillas A^6,7.

Abstract

The cellular mechanisms controlling cell fate in self-renewal tissues remain unclear. Cell cycle failure often leads to an apoptosis anti-oncogenic response. We have inactivated Cdk1 or Polo-like-1 kinases, essential targets of the mitotic checkpoints, in the epithelia of skin and oral mucosa. Here, we show that inactivation of the mitotic kinases leading to polyploidy in vivo, produces a fully differentiated 

 

 

epithelium. Cells within the basal layer aberrantly differentiate and contain large or various nuclei. Freshly isolated KO cells were also differentiated and polyploid. However, sustained metaphase arrest downstream of the spindle anaphase checkpoint (SAC) due to abrogation of CDC20 (essential cofactor of anaphase-promoting complex), impaired squamous differentiation and resulted in apoptosis. Therefore, upon prolonged arrest keratinocytes need to slip beyond G2 or mitosis in order to initiate differentiation. The results altogether demonstrate that mitotic checkpoints drive squamous cell fate towards differentiation or apoptosis in response to genetic damage.

https://www.ncbi.nlm.nih.gov/pubmed/32080348




 

IDIVAL REDUCE SU PLANTILLA DE INVESTIGACIÓN

Nuestro centro está dejando de estabilizar contratos de Investigación, y reduciendo personal propio. El Idival se nutre fundamentalmente de Investigadores del Hospital de Valdecilla y de la Universidad de Cantabria, así como investigadores contratados por el propio Instituto.

La pérdida de contratos de investigación pone en riesgo proyectos de biomedicina financiados por organismos públicos y asociaciones no gubernamentales.

https://www.eldiariomontanes.es/cantabria/lamentable-tire-basura-20200119191825-ntvo.html

https://www.eldiariomontanes.es/cantabria/idival-confirma-puede-20200121212119-ntvo.html

BECA PREDOCTORAL DE LA ASOCIACIÓN ESPAÑOLA CONTRA EL CÁNCER

La Asociación Española Contra el Cáncer (AECC) ha otorgado a Jesús Galán beca de doctorado para realizar proyecto de investigación y Tesis doctoral sobre cáncer epidermoide de pulmón en nuestro Grupo.

Jesús ha obtenido una de las dos becas en Cantabria. Estas son las primeras becas concedidas por la AECC en la región. Un hito conseguido gracias al esfuerzo de los donantes y de los responsables de la Asociación. Desde nuestro Grupo damos las gracias y un aplauso a todos ellos.
https://www.eldiariomontanes.es/cantabria/jovenes-reciben-sendas-20200114225249-nt.html

NONLETHAL ULTRAVIOLET LIGHT (UV) INDUCES SQUAMOUS DIFFERENTIATION

NEW WORK IN CELL DEATH AND DISEASE -OPEN ACCESS

The skin might maintain homeostasis in spite to daily exposure to UV light thanks to this mechanism.


Cell Death & Disease  volume 9, Article number: 1094 (2018)
https://www.nature.com/articles/s41419-018-1130-8

Sublethal UV irradiation induces squamous differentiation via a p53-independent, DNA damage-mitosis checkpoint

de Pedro I, Alonso-Lecue P, Sanz-Gómez N, Freije A, Gandarillas A
The epidermis is a self-renewal epithelium continuously exposed to the genotoxic effects of ultraviolet (UV) light, the main cause of skin cancer. Therefore, it needs robust self-protective mechanisms facing genomic damage. p53 has been shown to mediate apoptosis in sunburn cells of the epidermis. However, epidermal cells daily receive sublethal mutagenic doses of UV and massive apoptosis would be deleterious. We have recently unravelled an anti-oncogenic keratinocyte DNA damage-differentiation response to cell cycle stress. We now have studied this response to high or moderate single doses of UV irradiation. Whereas, as expected, high levels of UV induced p53-dependent apoptosis, moderate levels triggered squamous differentiation. UV-induced differentiation was not mediated by endogenous p53. Overexpression of the mitosis global regulator FOXM1 alleviated the proliferative loss caused by UV. Conversely, knocking-down the mitotic checkpoint protein Wee1 drove UV-induced differentiation into apoptosis. Therefore, the results indicate that mitosis checkpoints determine the response to UV irradiation. The differentiation response was also found in cells of head and neck epithelia thus uncovering a common regulation in squamous tissues upon chronic exposure to mutagens, with implications into homeostasis and disease.

On the press

NEW WORK ON RARE DISEASE IN SCIENTIFIC REPORTS -OPEN ACCESS

Primary cell cultures have an enormous mostly unexplored potential on rare diseases. Having the possibility to amplify and store cells from the patient allows genetic and cell behavioural studies. This allows not only identification of the associated mutation, leading to diagnosis, but also investigating the molecular and cellular mechanisms underlying the disease. Our work just out in Scientific Reports is an illustration of this potential.

https://www.nature.com/articles/s41598-018-36859-2

Cellular and animal models of skin alterations in the autism-related ADNP syndrome

Mollinedo P^1,2, Kapitansky O³, Gonzalez-Lamuño D^4,2, Zaslavsky A³, Real P⁵, Gozes I³, Gandarillas A⁶, Fernandez-Luna JL^7,8

Scientific Reportsvolume 9, Article number: 736 (2019) | Download Citation

 

Abstract

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy control. Adnp haploinsufficient mice (Adnp^+/−) mimicked the human condition showing reduced dermal thickness. Intranasal administration of NAP significantly increased dermal thickness and normalized the levels of cell cycle and differentiation markers. Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients.