TUMOUR SUPPRESSION GROUP

Vice-Direction of Basic Research
TUMOUR SUPPRESSION
GROUP
Molecular Oncology Programme | Tumour Suppression Group
Manuel Serrano
Group Leader
Staff Scientists
Han Li ( until May ), Susana Llanos,
Cristina Pantoja
Post-Doctoral Fellows
María Abad, Timothy Cash, Pablo J.
Fernández-Marcos, Cian J. Lynch,
Daniel Muñoz, Gianluca Varetti ( since
August )
Graduate Students
Noelia Alcázar, Elena LópezGuadamillas, Lucía Morgado-Palacín,
Lluc Mosteiro, Adelaida R. Palla ( until
June ), Dafni Chondronasiou ( since
October ), Raquel Bernad
Technician
Maribel Muñoz ( since October )
Visiting Scientist
Liming Gui ( since March )
OVERVIEW
Tumour suppressors are genes that can prevent the development
of cancer. All our cells have a functional set of these genes.
However, despite their efficient protection against cancer, these
genes can become defective over time. The affected cells thus
become partially unprotected from cancer and, upon additional
mutations in other genes, can give rise to cancer.
Understanding how tumour suppressor genes work may help us
to design drugs that block cancer. Our Group also manipulates
the mouse genome to create novel alterations that increase or
decrease tumour suppression potency.
SCIENTIFIC REPORT 2014
The goals of our Group are :
ɗɗ To understand the mechanisms of tumour suppression and
to identify new tumour suppressor regulators .
ɗɗ To study the interplay between tumour suppression and ageing .
ɗɗ To analyse the involvement of tumour suppressors in the
regulation of metabolism and the protection from metabolic
damage .
ɗɗ To characterise cellular senescence as a tumour suppression
mechanism.
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ɗɗ To investigate cellular pluripotency and the involvement of
tumour suppressors in the regulation of reprogramming to
induced pluripotent stem ( iPS ) cells .
ɗɗ To explore the role( s ) of cell plasticity in cancer, in tissue
regeneration, and in ageing.
SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
“ This year, we have obtained further
evidence linking pluripotency
genes to cancer. We have identified
compounds that activate p53
without inflicting DNA damage. And,
finally, we have reported the first
DNA sequence analysis of families
with unusual longevity.”
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Vice-Direction of Basic Research
Molecular Oncology Programme | Tumour Suppression Group
RESEARCH HIGHLIGHTS
Cancer and pluripotency
NANOG is a key pluripotency transcription factor in embryonic
stem cells ( ESC ), whose role in adult tissues and cancer is still
largely unexplored.
NANOG is linked to tumours derived from stratified epithelia. We
have found that NANOG is selectively expressed in stratified
epithelia, including the skin, the oesophagus, and external
mucosas such as the tongue ( FIGURE 1 ). Interestingly, genetic
overexpression of NANOG in mice selectively affected stratified
epithelia, where it produced an increase in cellular proliferation
and hyperplasia. NANOG promotes cell proliferation in these
tissues by binding and activating the promoter of the AURKA
gene, which encodes the mitotic factor Aurora kinase A. In
collaboration with the CNIO Cell Division and Cancer Group,
we have shown that genetic overexpression of AURKA in mice
recapitulates the same effects as NANOG in the oesophagus.
Importantly, NANOG and AURKA levels are positively correlated
in oesophageal and head-and-neck squamous cell carcinomas
( SCCs ), and inactivation of NANOG in SCC cells reduces their
proliferation.
Figure 2 The acridine derivative CID-765471 does
not induce DNA damage ( visualised by immunofluorescence of gH2A.X ), but it efficiently activates
p53 ( visualised by immunofluorescence of p53 ). As
a control, the genotoxic chemotherapeutic agent
doxorubicin ( DOXO ) produces severe DNA damage.
Figure 1 Histological section of the mouse tongue ( dorsal surface )
stained with an anti-NANOG antibody ( brown nuclei ). The wavy layer
of cells with brown nuclei ( expressing NANOG ) corresponds to the basal
layer that contains the epithelial stem cells.
NANOG promotes squamous cell carcinoma. A direct link between
NANOG and SCCs had yet to be established. Interestingly,
inducible overexpression of NANOG in mouse skin epithelia
favours the malignant conversion of skin tumours induced by
chemical carcinogenesis, leading to increased SCC formation.
Gene expression analyses in pre-malignant skin indicated that
NANOG induces genes associated to epithelial-mesenchymal
transition ( EMT ). Endogenous NANOG binds to the promoters of
these genes and induces EMT features in primary keratinocytes.
These results provide direct in vivo evidence for the oncogenic
role of NANOG in stratified epithelia.
that NANOGP8 is expressed in many human cancer cells and
that it is as active as NANOG1 in promoting reprogramming to
pluripotency. Therefore, NANOGP8 can contribute to cancer,
possibly by promoting cell de-differentiation and/or plasticity.
Ribosomal stress and cancer
Reprogramming activity of NANOGP8 : a NANOG family
member widely expressed in cancer. The human genome contains
11 NANOG paralogs, of which only NANOG1, NANOG2 and
NANOGP8 encode full-length proteins. In collaboration with the
CNIO Genes, Development and Disease Group, we have found
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PUBLICATIONS
Muñoz-Espín D, Serrano M ( 2014 ). Cellular
senescence : from physiology to pathology. Nat Rev Mol Cell Biol 15, 482-496.
García-Rodríguez JL, Barbier-Torres L,
Fernández-Álvarez S, Juan VG, Monte MJ,
Halilbasic E, Herranz D, Alvarez L, Aspichueta P, Marín JJ, Trauner M, Mato JM,
Serrano M, Beraza N, Martínez-Chantar ML
SCIENTIFIC REPORT 2014
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( 2014 ). SIRT1 controls liver regeneration
by regulating BA metabolism through
FXR and mTOR signaling. Hepatology
59, 1972-1983.
Piazzolla D, Palla AR, Pantoja C, Cañamero
M, de Castro IP, Ortega S, Gómez-López
G, Dominguez O, Megías D, Roncador
G, Luque-Garcia JL, Fernandez-Tresguerres B, Fernandez AF, Fraga MF,
Rodriguez-Justo M, Manzanares M,
is a non-genotoxic mechanism that results in free ribosomal
protein RPL11, which binds and inhibits HDM2, thereby
activating p53. In collaboration with the CNIO Experimental
Therapeutics Programme, we have identified a group of acridines
that efficiently produce nucleolar disruption and activate p53,
without inflicting DNA damage ( FIGURE 2 ). These acridines
inhibit the transcription of the ribosomal RNA genes in a process
that includes the selective degradation of the RPA194 subunit
of RNA polymerase I. Our findings provide the basis for nongenotoxic chemotherapeutic approaches that selectively target
the nucleolus.
Genetics of human longevity
Genotoxic chemotherapeutic agents produce lasting mutagenic
damage to the organism. To circumvent this serious drawback,
there is great interest in identifying chemotherapeutic agents that
activate p53 in a non-genotoxic manner. Nucleolar disruption
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Sánchez-Carbayo M, García-Pedrero
JM, Rodrigo JP, Malumbres M, Serrano M
( 2014 ). Lineage-restricted function of the
pluripotency factor NANOG in stratified
epithelia. Nat Commun 5, 4226.
Serrano M ( 2014 ). Senescence helps regeneration. Dev Cell 31, 671-672.
Palla AR, Piazzolla D, Abad M, Li H,
Dominguez O, Schonthaler HB, Wagner
EF, Serrano M ( 2014 ). Reprogramming
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activity of NANOGP8, a NANOG family member widely expressed in cancer.
Oncogene 33, 2513-2519.
Beiroa D, Imbernon M, Gallego R, Senra A,
Herranz D, Villaroya F, Serrano M, Fernø J,
Salvador J, Escalada J, Dieguez C, Lopez
M, Frühbeck G, Nogueiras R ( 2014 ). GLP-1
Agonism Stimulates Brown Adipose Tissue
Thermogenesis and Browning Through Hypothalamic AMPK. Diabetes 63, 3346-3358.
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CEGEN Unit, the CNIO Genomics Core Unit and the Spanish
Network of Ageing and Frailty ( RETICEF ), we have sequenced
a total of 7 exomes from exceptionally long-lived individuals
(>100 yrs old ) that come from 3 separate families with at least
2 centenarian siblings. We focused on rare functional variants
( RFVs ) and only 1 gene, APOB, carried RFVs in all members of
the three families. Proteins APOB and APOE are components
of lipoproteins specialised in the transport of cholesterol and
triglycerides. Interestingly, variants in these 2 genes, APOB and
APOE, had been previously associated with human longevity. We
have also identified candidate longevity genes shared between
2 families or within individual families. Our work provides a
catalogue of candidate genes that could contribute to exceptional
familial longevity. s
Exceptional longevity ( EL ) is a rare phenotype that can cluster
in families. In collaboration with the CNIO Human Genotyping-
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Pulido R et al. ( incl. Serrano ) ( 2014 ). A
unified nomenclature and amino acid
numbering for human PTEN. Sci Signal
7, pe15.
Rojo AI, Rada P, Mendiola M, Ortega-Molina A, Wojdyla K, Rogowska-Wrzesinska
A, Hardisson D, Serrano M, Cuadrado A
( 2014 ). The PTEN/NRF2 Axis Promotes
Human Carcinogenesis. Antioxid Redox
Signal 21, 2498-2514.
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Vilas J, Ferreirós A, Carneiro C, Morey L, Da
Silva-Álvarez S, Fernandes T, Abad M, di
Croce L, Hochedlinger K, García-Caballero
T, Serrano M, Rivas C, Vidal A, Collado M
( 2014 ). Transcriptional regulation of Sox2
by the retinoblastoma family of pocket
proteins. Oncotarget 6, 2992-3002.
Cash TP, Pita G, Domínguez O, Alonso MR,
Moreno LT, Borrás C, Rodríguez-Mañas L,
Santiago C, Garatachea N, Lucia A, Avella-
SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
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na JA, Viña J, González-Neira A, Serrano
M ( 2014 ). Exome sequencing of three
cases of familial exceptional longevity.
Aging Cell 13, 1087-1090.
Morgado-Palacin L, Llanos S, Urbano M,
Blanco-Aparicio C, Megias D, Pastor J,
Serrano M ( 2014 ). Non-genotoxic activation of p53 through the RPL11-dependent
ribosomal stress pathway. Carcinogenesis
35, 2822-2830.
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Boutant M, Joffraud M, Kulkarni S,
García-Casarrubios E, Garcia-Roves P, Fernandez-Marcos P, Valverde AM, Serrano M,
Cantó C ( 2014 ). SIRT1 enhances glucose
tolerance by potentiating brown adipose
tissue function. Mol Metab 4, 118-131.
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