Marcos Malumbres

Marcos Malumbres
Centro Nacional de Investigaciones Oncológicas | CNIO · Molecular Oncology Programme

Ph.D.

About

316
Publications
58,685
Reads
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24,253
Citations
Introduction
Cell cycle, mitosis, microRNAs. Molecular and Cell Biology. Cancer Biology. Breast Cancer. Pluripotency
Additional affiliations
January 2005 - present
Centro Nacional de Investigaciones Oncológicas
Position
  • Centro Nacional de Investigaciones Oncológicas (CNIO)
Description
  • Group Leader
January 2000 - present
Universidad Autónoma de Madrid
Description
  • Honorary Professor
January 1998 - December 2004
Centro Nacional de Investigaciones Oncológicas (CNIO)
Description
  • Mariano Barbacid's group

Publications

Publications (316)
Article
Full-text available
Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and maximum tolerated dose (MTD) of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase 1 clinical...
Preprint
Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1 , the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old femal...
Article
Chromosome segregation requires that centromeres properly attach to spindle microtubules. This essential step regulates the accuracy of cell division and therefore must be precisely regulated. One of the main centromeric regulatory signaling pathways is the Haspin-H3T3ph-chromosomal passenger complex (CPC) cascade, which is responsible for the recr...
Article
BACKGROUND: Metastatic breast cancer (mBC) remains an incurable disease and is the cause of nearly all deaths related to BC. Next-generation sequencing technologies are allowing the application of personalized targeted molecular therapies, thereby improving outcomes in breast cancer patients. However, they are not routinely used in the clinic and t...
Article
Full-text available
Alteration of centrosome function and dynamics results in major defects during chromosome segregation and is associated with primary autosomal microcephaly (MCPH). Despite the knowledge accumulated in the last few years, why some centrosomal defects specifically affect neural progenitors is not clear. We describe here that the centrosomal kinase PL...
Preprint
Chromosome segregation requires that centromeres properly attach to spindle microtubules. This is an essential step towards the accuracy of cell division and therefore must be precisely regulated in both mitosis and meiosis. One of the main centromeric regulatory signaling pathways is the Haspin-H3T3ph-chromosomal passenger complex (CPC) cascade, w...
Article
Full-text available
Congenital microcephaly (MCPH) is a neurodevelopmental disease associated to mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRIS...
Article
Full-text available
Pluripotent stem cells (PSCs) have proven to be an essential tool in many research fields including basic cell biology, development, or human disease. In addition, we are only starting to see their potential in regenerative medicine. Manipulation and culture of PSCs, however, imposes limitations in the quality of these cells and their ability to di...
Article
Chemical inhibitors of the deubiquitinase USP7 are currently being developed as anticancer agents based on their capacity to stabilize P53. Regardless of this activity, USP7 inhibitors also generate DNA damage in a p53-independent manner. However, the mechanism of this genotoxicity and its contribution to the anticancer effects of USP7 inhibitors a...
Article
Cell division requires the regulation of karyokinesis and cytokinesis, which includes an essential role of the achromatic spindle. Although the functions of centrosomes are well characterised in somatic cells, their role during vertebrate spermatogenesis remains elusive. We have studied the dynamics of the meiotic centrosomes in male mouse during b...
Preprint
Full-text available
The AKT-mTOR pathway is a central regulator of cell growth and metabolism. Upon sustained mTOR activity, AKT activity is attenuated by a feedback loop that restrains upstream signaling. However, how cells control the signals that limit AKT activity is not fully understood. Here we show that MASTL/Greatwall, a cell-cycle kinase that supports mitosis...
Article
Full-text available
Tumorigenesis induces actin cortex remodeling, which makes cancerous cells softer. Cell deformability is largely determined by myosin-driven cortical tension and actin fiber architecture at the cell cortex. However, it is still unclear what the weight of each contribution is, and how these contributions change during cancer development. Moreover, l...
Article
Full-text available
Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiati...
Preprint
Full-text available
Cellular reprogramming from somatic to pluripotent cells is the basis for multiple applications aimed to replace damaged tissues in regenerative medicine. However, this process is limited by intrinsic barriers that are induced in response to reprogramming factors. In this manuscript we report that miR-203, a microRNA with multiple functions in diff...
Preprint
Full-text available
Autosomal Recessive Primary Microcephaly (MCPH) is a rare disease associated to proteins involved in centrosomal and spindle dynamics including Cep135 (MCPH8). Although Cep135 has been associated to centriolar assembly, the mechanisms associated to the pathogenesis underlying MCPH8 mutations are unclear. By using a series of CRISPR/Cas9-edited muri...
Article
Inhibiting the cell-cycle kinases CDK4 and CDK6 results in significant therapeutic effect in patients with advanced hormone-positive breast cancer. The efficacy of this strategy is, however, limited by innate or acquired resistance mechanisms and its application to other tumor types is still uncertain. Here, through an integrative analysis of sensi...
Article
Proper progression throughout the cell division cycle depends on the expression level of a family of proteins known as cyclins, and the subsequent activation of cyclin-dependent kinases (Cdks). Among the numerous members of the mammalian cyclin family, only a few of them, cyclins A, B, C, D and E, are known to display critical roles in the cell cyc...
Article
Full-text available
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...
Article
Inhibition of the cell-cycle kinases CDK4 and CDK6 is now part of the standard treatment in advanced breast cancer. CDK4/6 inhibitors, however, are not expected to cooperate with DNA-damaging or antimitotic chemotherapies as the former prevent cell-cycle entry, thus interfering with S-phase- or mitosis-targeting agents. Here, we report that sequent...
Chapter
During the past several decades, investigators have uncovered a wealth of information about the proteins that control the division of human cells. A key finding is that deregulation of the cell cycle machinery and/or its checkpoints is a universal alteration in human cancer. Because the basic machinery that controls the cell cycle is similar in all...
Article
Full-text available
The human MASTL (Microtubule-associated serine/threonine kinase-like) gene encodes an essential protein in the cell cycle. MASTL is a key factor preventing early dephosphorylation of M-phase targets of Cdk1/CycB. Little is known about the mechanism of MASTL activation and regulation. MASTL contains a non-conserved insertion of 550 residues within i...
Preprint
Full-text available
Full differentiation potential along with self-renewal capacity is a major property of pluripotent stem cells (PSCs). However, the differentiation capacity frequently decreases during expansion of PSCs in vitro. We show here that transient exposure to a single microRNA, expressed at early stages during normal development, improves the differentiati...
Article
To celebrate this year’s Peer Review Week theme, “Quality in Peer Review,” we asked editors across Cell Press to nominate some of their best reviewers to give their philosophies on peer reviewing.
Article
Full-text available
The recent availability of somatic haploid cell lines has provided a unique tool for genetic studies in mammals. However, the percentage of haploid cells rapidly decreases in these cell lines, which we recently showed is due to their overgrowth by diploid cells present in the cultures. Based on this property, we have now performed a phenotypic chem...
Article
Full-text available
FBXW7 is a driver gene in T-cell lymphoblastic neoplasia acting through proteasome degradation of key proto-oncogenes. FBXW7 encodes three isoforms, α, β and γ, which differ only in the N-terminus. In this work, massive sequencing revealed significant downregulation of FBXW7 in a panel of primary T-cell lymphoblastic lymphomas characterised by the...
Article
Full-text available
The cell cycle is a tightly regulated process that is controlled by the conserved cyclin-dependent kinase (CDK)–cyclin protein complex¹. However, control of the G0-to-G1 transition is not completely understood. Here we demonstrate that p38 MAPK gamma (p38γ) acts as a CDK-like kinase and thus cooperates with CDKs, regulating entry into the cell cycl...
Article
Full-text available
Fusions transcripts have been proven to be strong drivers for neoplasia-associated mutations, although their incidence in T-cell lymphoblastic lymphoma needs to be determined yet. Using RNA-Seq we have selected 55 fusion transcripts identified by at least two of three detection methods in the same tumour. We confirmed the existence of 24 predicted...
Article
Full-text available
Aurora A is a serine/threonine kinase whose role in cell cycle progression and tumour generation has been widely studied. Recent work has revealed an unexpected function for Aurora A during CD4+ T cell activation and, also, in graft versus host disease development. However, it remains unknown whether Aurora A is involved in CD8+ T cell effector fun...
Data
Video S4. Mitosis in Gwl siRNA-Transfected, MK1775-Treated, and Gwl siRNA/STLC-Treated Cells, Relating to Figures 4F and 4G As in Video S3. Left Panes: Cells transfected with Gwl siRNA, Middle Panels: Cells treated with 1 μM MK1775. Right Panel: Cells transfected with Gwl siRNAand treated with 5 μM STLC before initiating the imaging sequence.
Data
Video S1. Synchronous Mitotic Entry and Exit in HeLa cdk1as Cells, Related to Figure 2B HeLa cdk1as cells were incubated for 20 hours with 2 μM 1NM-PP1 and 1 μM sirDNA. Inhibitor-containing medium was removed by washing the cells five times in drug-free medium. Finally, cells were taken up in medium containing 25 μM MG132 and 1 μM sirDNA and image...
Data
Video S2. Examples of Cells after Re-addition of 1NM-PP1 following Release, Related to Figure 4B HeLa cdk1as cells with endogenously tagged CyclinB1-GFP were released from 1NM-PP1 arrest as in Video S1 and retreated with 1 μM 1NM-PP1 25 minutes after initial release. Left panels show sirDNA (Far-red), middle panels show Cyclin B1-GFP and right pan...
Data
Video S3. Mitosis in Ctr siRNA-Transfected and Gwl siRNA-Transfected HeLa Cells after Wee1 Inhibition, Related to Figures 4F and 4G Left Panels: HeLa cells transfected with Ctr siRNA were imaged in the presence of sirDNA 48 hours later. Right Panels: HeLa cells transfected with Gwl siRNA and treated with 1 μM MK1775.
Article
Full-text available
Distinct protein phosphorylation levels in interphase and M phase require tight regulation of Cdk1 activity [1, 2]. A bistable switch, based on positive feedback in the Cdk1 activation loop, has been proposed to generate different thresholds for transitions between these cell-cycle states [3, 4, 5]. Recently, the activity of the major Cdk1-countera...
Article
Errors in chromosome segregation during female meiosis I occur frequently, and aneuploid embryos account for 1/3 of all miscarriages in humans [1]. Unlike mitotic cells that require two Aurora kinase (AURK) homologs to help prevent aneuploidy (AURKA and AURKB), mammalian germ cells also require a third (AURKC) [2, 3]. AURKA is the spindle-pole-asso...
Article
MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the th...
Article
CDK4/6 inhibitors have shown a great potential in the new armamentarium against cancer. However, their effect as single agents is limited and the hopes are on new combinatory strategies. Recent data suggest that inhibiting mTOR may significantly cooperate with cell cycle arrest in a variety of cancers.
Article
Full-text available
Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mamm...
Article
Full-text available
Polo-like kinase 1 (Plk1) is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene and an attractive cancer target. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse model we report here that Plk1 overexpression results in abnormal chromosome segregation and cytoki...
Article
Tumor formation is a multi-step process during which cells acquire genetic and epigenetic changes until they reach a fully transformed state. We show that CDK6 contributes to tumor formation by regulating transcriptional responses in a stage-specific manner. In early stages CDK6 kinase induces a complex transcriptional program to block p53 in hemat...
Conference Paper
Full-text available
Introduction Pancreatic Ductal Adenocarcinoma (PDAC) is among the deadliest human cancers with a 5 year survival rate of less than 5% using the standard of care gemcitabine/nab-paclitaxel. The most frequently disrupted genes in PDACs are first K-RAS and second CDKN2A, which encodes the cyclin-dependent kinase (CDK)4/6 inhibitor p16. Recently, CDK4/...
Conference Paper
Full-text available
Introduction Mastl, also known as Greatwall, is a protein kinase essential for proper chromosome condensation and progression through mitosis and meiosis. It belongs to the AGC kinase family and, particularly, presents a non-conserved insertion of 550 aa at the corresponding T-activation loop site in the C-lobe (usually 20–30 aa). This non-conserve...
Conference Paper
Introduction: T-cell lymphoblastic leukaemia/lymphoma (T-ALL/T-LBL) is a type of hematological cancer prevalent in the childhood. Different genes have been related with the development of this disease including the tumor suppressor gene FBXW7, which plays an important role acting through the proteasome degradation of key proto-oncogenes. In this wo...
Article
Full-text available
Background: Precursor T-cell lymphoblastic lymphomas (T-LBL) are rare aggressive hematological malignancies that mainly develop in children. As in other cancers, the loss of cell cycle control plays a prominent role in the pathogenesis in these malignancies that is primarily attributed to loss of CDKN2A (encoding protein p16INK4A). However, the im...
Article
Full-text available
The cellular response to DNA damage is essential for maintaining the integrity of the genome. Recent evidence has identified E2F7 as a key player in DNA damage-dependent transcriptional regulation of cell-cycle genes. However, the contribution of E2F7 to cellular responses upon genotoxic damage is still poorly defined. Here we show that E2F7 repres...
Preprint
Full-text available
Polo-like kinase 1 (Plk1) is a protein kinase currently considered as an attractive cancer target due to its critical role in the cell division cycle. Plk1 is overexpressed in a wide spectrum of human tumors, being frequently considered as an oncogene. However, its contribution to tumor development is unclear. Using a new inducible knock-in mouse m...
Preprint
Full-text available
Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mamm...
Article
Full-text available
PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase...