Vice-Direction of Basic Research
CELL DIVISION AND
CANCER GROUP
Molecular Oncology Programme | Cell Division And Cancer Group
Marcos Malumbres
Group Leader
Staff Scientists
Mónica Álvarez, Guillermo de Cárcer,
Ignacio Pérez de Castro, Eva Porlan
Post-Doctoral Fellows
Begoña Hurtado ( since October ),
Carolina Maestre, María Salazar
Graduate Students
Ana F. Batalha Martins, Elena
Doménech ( until May ), Alejandra
González ( until January ), María
Maroto, Diego Martínez Alonso
( since September ), Belén Sanz, María
Sanz, Marianna Trakala ( until May )
Technicians
David Partida, Elisabet Zapatero
( since September ) ( TS )*
Titulado Superior ( Advanced Degree )
*
OVERVIEW
The Cell Division and Cancer Group is interested in deciphering
the mechanisms by which cell division and cell proliferation
are regulated. During the last few years, we have generated and
characterised different mouse models in order to understand
the relevance of several cell cycle regulators in the control of
cell division and tissue physiology ; these include cell cycle
kinases and phosphatases, and proteins involved in ubiquitindependent degradation. Our interests are : i ) to understand
the basic control mechanisms that regulate the cell division
cycles ; ii ) to characterise the physiological and therapeutic
consequences of cell cycle deregulation ; iii ) characterising the
function of microRNAs in cell biology and tumour development,
and iv ), understanding how progenitor cells and cancer stem
cells control their self-renewal and proliferative properties. As
a final goal, we aim to generate information that may be useful
towards improving therapeutic strategies against cancer cell
proliferation.
ANNUAL REPORT 2015
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SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
“ In 2015, we investigated the
relevance of several mitotic
regulators during cancer
progression and therapy. We have
also described the metabolic
changes imposed by microtubule
poisons that are used to treat cancer
and their therapeutic relevance.”
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Vice-Direction of Basic Research
Molecular Oncology Programme | Cell Division And Cancer Group
RESEARCH HIGHLIGHTS
Figure 2 A metabolic switch during
mitotic arrest. The extenuation of
mitochondria during mitotic arrest
results in the activation of an AMPKPFKFB3-dependent pathway that
induces glycolysis for the generation
of energy and survival.
In vivo relevance of cell cycle inhibitors and replicative
stress
The mammalian cell cycle is regulated by at least 2 families of
inhibitors, the INK4 and Cip/Kip proteins. While elimination
of individual members of these families is a frequent finding in
human cancer, the consequences of eliminating this inhibitory
mechanism in mammalian cells have not yet been explored.
Using a combination of mutant alleles in the mouse, we have
now observed that a major physiological function of cell cycle
inhibitors is the prevention of replicative stress. In a mouse
model insensitive to INK4 proteins and deficient in p21Cip 1
and p27Kip 1, we observed that these inhibitors prevent the
accumulation of DNA damage due to replicative stress in
different tissues including the nervous system. Moreover,
ablation of these inhibitors prevents mouse development.
This effect is most likely due to the hyperactivation of cyclindependent kinases, since the replicative stress can be prevented
by slightly inhibiting the enzymatic activity of these proteins
( Quereda et al., 2015 ).
Oncogenic effect of Aurora kinases in cancer
Aurora kinases are enzymes involved in the regulation of mitosis.
These proteins are frequently overexpressed in human tumours
and are currently considered as putative cancer targets. Yet,
the effect of their overexpression in vivo is not well understood.
We generated a new mouse model in which endogenous Aurora
B can be overexpressed in a conditional manner ( GonzálezLoyola et al., 2015 ). Mice that overexpressed this kinase
developed a wide variety of tumours. The molecular and cellular
characterisation of these tumours suggested that Aurora B
overexpression not only induces chromosomal instability, as
previously expected, but also results in a dysfunctional p53
response, thus contributing to tumour development through
multiple mechanisms.
Regulation of the megakaryocyte cell cycle
The cell cycle is widely considered as a universal mechanism
for cell proliferation. However, some specialised cells display
variants of the consensus cell cycle and understanding these
differences may be crucial in the design of therapies against
specific malignancies. Using mouse models with specific
alterations in cell cycle regulators, we studied the relevance of
endoreplication and endomitosis ; two variants of the canonical
cell cycle, in megakaryocytes. These cells undergo multiple
rounds of genome amplification without generating daughter
cells, thus increasing their ploidy. We have identified several
ANNUAL REPORT 2015
Figure 1 Different variants of the
mammalian cell cycle are found
in mammals. Megakaryocytes
normally undergo endomitosis
by skipping late mitotic events.
In the absence of Cdk1, they
autophagy-dependent mitochondrial degradation and a dramatic
energetic deficit ( Doménech et al., 2015 ). The subsequent increase
in the AMP/ATP ratio results in the activation of the metabolic
sensor AMPK followed by phosphorylation and activation of
PFKFB3, an enzyme required for glycolysis. Thus, mitophagy
undergo repeated S-G phases
( endoreplication ), whereas the
DNA is replicated more than once
( re-replication ) in the absence of
both Cdk1 and Cdk2.
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mitotic kinases that, despite being essential for mitotic cell cycles
( such as the ones used by cancer cells ), are dispensable for the
polyploidisation of megakaryocytes, thereby providing some
new options for leukaemia treatment. Other kinases, such as
Plk1, are still essential for megakaryocytes and their inhibition
leads to thrombocytopaenia ( Trakala et al., 2015 ).
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Control of cellular metabolism in mitosis
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Microtubule poisons, such as taxanes, block mitosis and
eventually lead to cell death in a process frequently known as
mitotic catastrophe. However, some cells are able to bypass this
mitotic arrest and survive, thus contributing to chemo-resistance
to those therapies. We have recently observed that mitotic arrest
induces an early autophagic flux response, which results in
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PUBLICATIONS
Doménech E, Maestre C, Esteban-Martínez
L, Partida D, Pascual R, Fernández-Miranda
G, Seco E, Campos-Olivas R, Pérez M, Megias D, Allen K, López M, Saha AK, Velasco
G, Rial E, Méndez R, Boya P, Salazar-Roa
M, Malumbres M ( 2015 ). AMPK and PFKFB3 mediate glycolysis and survival in
response to mitophagy during mitotic
arrest. Nat Cell Biol 17, 1304-1316.
Huang J, Ikeuchi Y, Malumbres M, Bonni
A ( 2015 ). A Cdh1-APC/FMRP Ubiquitin
Signaling Link Drives mGluR-Dependent Synaptic Plasticity in the Mammalian
Brain. Neuron 86, 726-739.
Álvarez-Fernández M, Malumbres M
( 2015 ). An Atypical Oncogene Within the
Atypical E2Fs. J Natl Cancer I 107, djv180.
Esteban-Martínez L, Doménech E, Boya
P, Salazar-Roa M, Malumbres M ( 2015 ).
Mitophagy in mitosis : more than a myth.
Autophagy 11, 2379-2380.
Serra H, Chivite I, Angulo-Urarte A, Soler
A, Sutherland JD, Arruabarrena-Aristorena
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A, Ragab A, Lim R, Malumbres M, Fruttiger
M, Potente M, Serrano M, Fabra À, Viñals F,
Casanovas O, Pandolfi PP, Bigas A, Carracedo A, Gerhardt H, Graupera M ( 2015 ). PTEN
mediates Notch-dependent stalk cell arrest
in angiogenesis. Nat Commun 6, 7935.
Trakala M, Partida D, Salazar-Roa M,
Maroto M, Wachowicz P, de Cárcer G,
Malumbres M ( 2015 ). Activation of the
endomitotic spindle assembly checkpoint
and thrombocytopenia in Plk1-deficient
mice. Blood 126, 1707-1714.
Scheicher R, Hoelbl-Kovacic A, Bellutti F,
Tigan AS, Prchal-Murphy M, Heller G, Schneckenleithner C, Salazar-Roa M, Zöchbauer-Müller S, Zuber J, Malumbres M,
Kollmann K, Sexl V ( 2015 ). CDK6 as a key
regulator of hematopoietic and leukemic
stem cell activation. Blood 125, 90-101.
Trakala M, Rodríguez-Acebes S, Maroto
M, Symonds CE, Santamaría D, Ortega
S, Barbacid M, Méndez J, Malumbres
M. ( 2015 ). Functional reprogramming
of polyploidization in megakaryocytes.
Dev Cell 32, 155-167.
SPANISH NATIONAL CANCER RESEARCH CENTRE, CNIO
can be considered as a critical effector of the therapeutic effect
of mitotic therapies, while both AMPK and PFKFB3 are critical
for survival. The manipulation of these molecular routes may
have therapeutic benefits in the presence of microtubule poisons
( Esteban-Martinez et al., 2015 ). s
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Malumbres M. ( 2015 ) Keeping order in
anaphase. Dev Cell 35, 403-404.
Penas C, Govek EE, Fang Y, Ramachandran
V, Daniel M, Wang W, Maloof ME, Rahaim
RJ, Bibian M, Kawauchi D, Finkelstein D,
Han JL, Long J, Li B, Robbins DJ, Malumbres M, Roussel MF, Roush WR, Hatten
ME, Ayad NG ( 2015 ). Casein kinase 1d is
an APC/C( Cdh1 ) substrate that regulates
cerebellar granule cell neurogenesis. Cell
Rep 11, 249-260.
Quereda V, Porlan E, Cañamero M, Dubus
P, Malumbres M ( 2015 ). An essential role
for Ink4 and Cip/Kip cell-cycle inhibitors
in preventing replicative stress. Cell Death
Differ. PMID : 26292757.
Sánchez-Martínez R, Cruz-Gil S, Gómez de
Cedrón M, Álvarez-Fernández M, Vargas
T, Molina S, García B, Herranz J, Moreno-Rubio J, Reglero G, Pérez-Moreno M,
Feliú J, Malumbres M, Ramírez de Molina
A ( 2015 ). A link between lipid metabolism
and epithelial-mesenchymal transition
provides a target for colon cancer therapy.
Oncotarget. PMID : 26451612.
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González-Loyola A, Fernández-Miranda G, Trakala M, Partida D, Samejima K,
Ogawa H, Cañamero M, de Martino A,
Martínez-Ramírez Á, de Cárcer G, Pérez
de Castro I, Earnshaw WC, Malumbres M
( 2015 ). Aurora B overexpression causes
aneuploidy and p21Cip1 repression during tumor development. Mol Cell Biol 35,
3566-3578.
Búa S, Sotiropoulou P, Sgarlata C, Borlado, LR, Eguren M, Domínguez O, Ortega
S, Malumbres M, Blanpain C, Méndez J
( 2015 ). Deregulated expression of Cdc6
in the skin facilitates papilloma formation
and affects the hair growth cycle. Cell
Cycle 14, 3897-3907.
AWARDS AND RECOGNITION
Board Member, Scientific Foundation of
the Spanish Association Against Cancer
( AECC ).
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