Review
Oncology
Lucia Paolini, Sajjad Hussain, Paul J. J. Galardy
Summary: Genomic instability is a central factor in the pathogenesis of human cancer. Most of the time, chromosome instability negatively affects cellular fitness, but in cancer it is usually associated with worse prognosis. Neuroblastoma, a common solid tumor in children, has two distinct patterns of genomic instability, with whole-chromosome aneuploidy associated with better prognosis.
FRONTIERS IN ONCOLOGY
(2022)
Review
Pharmacology & Pharmacy
Styliani Iliaki, Rudi Beyaert, Inna S. Afonina
Summary: PLK1 is a Ser/Thr kinase that plays crucial roles in cell cycle regulation, DNA damage response, apoptosis, and cancer progression. Overexpression of PLK1 is associated with poor prognosis in cancer, making it an attractive therapeutic target.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Jing Li, Shunya Ohmura, Aruna Marchetto, Martin F. Orth, Roland Imle, Marlene Dallmayer, Julian Musa, Maximilian M. L. Knott, Tilman L. B. Holting, Stefanie Stein, Cornelius M. Funk, Ana Sastre, Javier Alonso, Felix Bestvater, Merve Kasan, Laura Romero-Perez, Wolfgang Hartmann, Andreas Ranft, Ana Banito, Uta Dirksen, Thomas Kirchner, Florencia Cidre-Aranaz, Thomas G. P. Gruenewald
Summary: The study shows that targeting PRC1 or PLK1 can induce fatal genomic instability and tumor regression in EwS model. EWSR1-FLI1, an oncogenic transcription factor specific to EwS, hijacks PRC1 to promote tumor growth by binding to GGAA microsatellite. High PRC1 expression creates a therapeutic vulnerability towards PLK1 inhibition, leading to repression of even chemo-resistant EwS cells by triggering mitotic catastrophe.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
My Anh Truong, Paula Cane-Gasull, Sippe G. de Vries, Wilco Nijenhuis, Rene Wardenaar, Lukas C. Kapitein, Floris Foijer, Susanne M. A. Lens
Summary: Various cancer types exhibit characteristic and recurrent aneuploidy patterns. The origins of these cancer type-specific karyotypes are still unknown, partly because introducing or eliminating specific chromosomes in human cells still poses a challenge. Here, we describe a novel strategy to induce mis-segregation of specific chromosomes in different human cell types. Our kinesin-based strategy opens the possibility to investigate the immediate cellular responses to specific aneuploidies in different cell types; an important step toward understanding how tissue-specific aneuploidy patterns evolve.
Review
Cell Biology
Zuzana Storchova
Summary: Eukaryotic cells are typically diploid, but aberrant chromosome numbers such as aneuploidy and polyploidy can occur due to mitotic failures. Recent research has shown that mitotic errors lead to extensive modifications of cellular processes, affecting proliferation, proteome balance, genome stability, and more. The cellular response to aneuploidy and polyploidy is viewed as a complex, tissue-specific network of events.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
Editorial Material
Cell Biology
Roberto Chiarle
Summary: Two companion papers in the Genes & Development journal used sophisticated mouse models to study the progression of aneuploidy from early phases to established tumors and found that while early non-tumoral cells exhibit random chromosomal gains, established tumors display a stereotypic karyotype with recurrent gains of only a few chromosomes, suggesting reproducible patterns of chromosomal changes induced by underlying mechanisms.
GENES & DEVELOPMENT
(2021)
Article
Biochemistry & Molecular Biology
Haiyu Song, Eun Ho Kim, Jihee Hong, Dasom Gwon, Jee Won Kim, Gyu-Un Bae, Chang-Young Jang
Summary: The centrosome forms a bipolar spindle during mitosis for faithful chromosome segregation. The DNA damage response (DDR) induces programmed spindle multipolarity and death in mitosis to prevent inheritance of DNA damage. Hornerin acts as a link between DDR and death in mitosis by forming a complex with checkpoint kinase 1 (Chk1) and polo-like kinase 1 (Plk1) to mediate phosphorylation at the polo-box domain (PBD) of Plk1. Hornerin mediates DDR-induced premature centriole disengagement through phosphorylation of Plk1 PBD, leading to spindle multipolarity. This study reveals the mechanism of how DDR eliminates mitotic cells with DNA damage to maintain genome integrity.
CELL DEATH AND DIFFERENTIATION
(2023)
Editorial Material
Biochemistry & Molecular Biology
Gian Paolo Tonini
Summary: Neuroblastoma is a pediatric cancer that can present as localized or metastatic disease. Patients with localized tumors tend to have better outcomes, possibly due to lower levels of chromosome instability (CIN), compared to patients with metastatic tumors.
Review
Biotechnology & Applied Microbiology
Xing Yan, Shan Mei Liu, Changhong Liu
Summary: Aneuploidy, a feature of most cancer cells, is characterized by an elevated rate of mis-segregation of chromosomes. Lung cancer, the leading cause of cancer-related deaths worldwide, shows extensive aneuploid changes in its genome map. Studying the role of aneuploidy in the evolution of lung cancer is of great significance for predicting prognosis and understanding the mechanisms of lung cancer development.
ONCOTARGETS AND THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Marzia Ognibene, Patrizia De Marco, Loredana Amoroso, Martina Fragola, Federico Zara, Stefano Parodi, Annalisa Pezzolo
Summary: Chromosomal instability (CIN) is a hallmark of most human cancers and can lead to losses or gains of chromosomes. This study evaluated the prognostic role of CIN in NB patients at diagnosis and found that high CIN values are negatively associated with survival of NB patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Marianna Trakala, Muskaan Aggarwal, Courtney Sniffen, Lauren Zasadil, Allison Carroll, Duanduan Ma, Xiaofeng A. Su, Darawalee Wangsa, Ashleigh Meyer, Cynthia J. Sieben, Jian Zhong, Pei-hsin Hsu, Glenn Paradis, Thomas Ried, Andrew Holland, Jan Van Deursen, Angelika Amon
Summary: Chromosome gains and losses are common in human cancers, but how they can counteract the effects of aneuploidy remains unclear. Research using mouse models suggests that clonal selection and specific gene properties can drive cancer development.
GENES & DEVELOPMENT
(2021)
Review
Cell Biology
Marin Barisic, Girish Rajendraprasad, Yulia Steblyanko
Summary: The spindle assembly checkpoint (SAC) is a surveillance mechanism that promotes accurate chromosome segregation in mitosis by sensing the attachment state of kinetochores. Current understanding of how SAC proteins are recruited to kinetochores in the absence of microtubule attachment and how attachments silence the SAC at the kinetochore is limited, requiring further investigation.
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Ivan Y. Iourov, Yuri B. Yurov, Svetlana G. Vorsanova, Sergei I. Kutsev
Summary: Chromosome instability (CIN) has been linked to aging and neurodegenerative diseases, with a possible role in cellular senescence and neuronal cell death. Despite the debate surrounding the occurrence of CIN in the aging brain, its impact on cellular aging and neurodegeneration is significant.
Article
Cell Biology
Conor P. Herlihy, Sabine Hahn, Nicole M. Hermance, Elizabeth A. Crowley, Amity L. Manning
Summary: Epigenetic modifications of histones at centromeres and pericentromeric chromatin are crucial for centromere structure and function. Increased localization of Suv39 and Suv420 at centromeres suppresses transcription, compromises Aurora B localization, and leads to errors in chromosome alignment and segregation.
JOURNAL OF CELL SCIENCE
(2021)
Review
Cell Biology
Jaroslav Kalous, Daria Aleshkina
Summary: Cells contain a diverse network of signaling and regulatory proteins to ensure the proper progression of cell division. A key regulator in this process is the enzyme polo-like kinase 1 (PLK1), which plays important roles in mitosis, meiosis, and cytokinesis. PLK1 controls various aspects of cell division, including nuclear envelope breakdown, centrosome maturation, spindle assembly, chromosome segregation, and cytokinesis. In mammalian oogenesis, PLK1 is essential for the resumption of meiosis and establishment of the meiotic spindle. Additionally, PLK1 regulates localized mRNA translation by phosphorylating and inhibiting the translational repressor 4E-BP1, a downstream target of the mTOR pathway.
Article
Hematology
Marianna Trakala, David Partida, Maria Salazar-Roa, Maria Maroto, Paulina Wachowicz, Guillermo de Carcer, Marcos Malumbres
Article
Biochemistry & Molecular Biology
Alejandra Gonzalez-Loyola, Gonzalo Fernandez-Miranda, Marianna Trakala, David Partida, Kumiko Samejima, Hiromi Ogawa, Marta Canamero, Alba de Martino, Angel Martinez-Ramirez, Guillermo de Carcer, Ignacio Perez de Castro, William C. Earnshaw, Marcos Malumbres
MOLECULAR AND CELLULAR BIOLOGY
(2015)
Article
Biochemistry & Molecular Biology
Paulina Wachowicz, Gonzalo Fernandez-Miranda, Carlos Marugan, Beatriz Escobar, Guillermo de Carcer
Article
Multidisciplinary Sciences
Noelia Blas-Rus, Eugenio Bustos-Moran, Ignacio Perez de Castro, Guillermo de Carcer, Aldo Borroto, Emilio Camafeita, Inmaculada Jorge, Jesus Vazquez, Balbino Alarcon, Marcos Malumbres, Noa B. Martin-Cofreces, Francisco Sanchez-Madrid
NATURE COMMUNICATIONS
(2016)
Article
Biochemistry & Molecular Biology
Guillermo de Carcer, Paulina Wachowicz, Sara Martinez-Martinez, Jorge Oller, Nerea Mendez-Barbero, Beatriz Escobar, Alejandra Gonzalez-Loyola, Tohru Takaki, Aicha El Bakkali, Juan A. Camara, Luis J. Jimenez-Borreguero, Xose R. Bustelo, Marta Canamero, Francisca Mulero, Maria de los Angeles Sevilla, Maria Jose Montero, Juan Miguel Redondo, Marcos Malumbres
Editorial Material
Genetics & Heredity
Guillermo de Carcer, Pablo Huertas, Andres J. Lopez-Contreras
Article
Multidisciplinary Sciences
Guillermo de Carcer, Sharavan Vishaan Venkateswaran, Lorena Salgueiro, Aicha El Bakkali, Kalman Somogyi, Konstantina Rowald, Pablo Montanes, Manuel Sanclemente, Beatriz Escobar, Alba de Martino, Nicholas McGranahan, Marcos Malumbres, Rocio Sotillo
NATURE COMMUNICATIONS
(2018)
Article
Cell Biology
Teresa Olbrich, Maria Vega-Sendino, Matilde Murga, Guillermo de Carcer, Marcos Malumbres, Sagrario Ortega, Sergio Ruiz, Oscar Fernandez-Capetillo
Article
Biochemistry & Molecular Biology
Natalia Sanz-Gomez, Isabel de Pedro, Beatriz Ortigosa, David Santamaria, Marcos Malumbres, Guillermo de Carcer, Alberto Gandarillas
CELL DEATH AND DIFFERENTIATION
(2020)
Article
Medicine, Research & Experimental
Sonia Solanes-Casado, Arancha Cebrian, Maria Rodriguez-Remirez, Ignacio Mahillo, Laura Garcia-Garcia, Anxo Rio-Vilarino, Natalia Banos, Guillermo de Carcer, Ana Monfort-Vengut, Victor Castellano, Maria Jesus Fernandez-Acenero, Jesus Garcia-Foncillas, Laura del Puerto-Nevado
Summary: New therapeutic targets have transformed the clinical management of colorectal cancer, with PLK1 inhibitors showing promise but facing challenges of drug resistance. In vitro generation and analysis of resistant cell lines revealed mechanisms such as AXL pathway activation and EMT, with simvastatin and drug combinations proving effective in resensitizing resistant cells. Targeting the mevalonate pathway emerges as a new strategy for overcoming PLK1 inhibitor resistance.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Jose Gonzalez-Martinez, Andrzej W. Cwetsch, Javier Gilabert-Juan, Jesus Gomez, Guillermo Garaulet, Paulina Schneider, Guillermo de Carcer, Francisca Mulero, Eduardo Caleiras, Diego Megias, Eva Porlan, Marcos Malumbres
Summary: This study reveals that the centrosomal kinase PLK1 regulates centrosome asymmetry and cell fate in neural progenitors. Loss of PLK1 activity leads to reduced asymmetry and increased expansion of neural progenitors, promoting cortical growth. However, deficiencies in MCPH proteins result in increased centrosome asymmetry and microcephaly.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Oncology
Donna M. Edwards, Dana K. Mitchell, Zahi Abdul-Sater, Ka-Kui Chan, Zejin Sun, Aditya Sheth, Ying He, Li Jiang, Jin Yuan, Richa Sharma, Magdalena Czader, Pei-Ju Chin, Yie Liu, Guillermo de Carcer, Grzegorz Nalepa, Hal E. Broxmeyer, D. Wade Clapp, Elizabeth A. Sierra Potchanant
Summary: The study highlights the importance of mitotic regulation in the development of malignancies associated with the FA pathway deficiency. By introducing heterozygosity of the spindle assembly checkpoint regulator Mad2 in Fancc-/- mice, researchers were able to create a mouse model that better replicates the high risk of myeloid malignancies seen in FA patients. This suggests that error-prone cell division may play a key role in cancer development in FA patients.
FRONTIERS IN ONCOLOGY
(2021)
Review
Pharmacology & Pharmacy
Ana Monfort-Vengut, Guillermo de Carcer
Summary: Rigosertib is a small-molecule compound currently in phase III clinical trials for the treatment of various myelodysplastic syndromes and leukemias. However, its clinical progress has been hindered by a lack of understanding of its mechanism of action.
Review
Cell Biology
Natalia Sanz-Gomez, Maria Gonzalez-Alvarez, Javier De Las Rivas, Guillermo de Carcer
Summary: Chromosome instability is a well-recognized characteristic of cancer, resulting in increased genetic variability of tumor cells, which facilitates cancer aggressiveness and poor prognosis. Whole-Genome Duplication (WGD) and subsequent polyploidy are main causes of chromosomal instability. Recent studies have revealed that WGD occurs in the early stages of cell transformation, enabling cells to later become aneuploid and drive cancer progression. However, other research suggests that polyploidy acts as a tumor suppressor by inducing cell cycle arrest, cell senescence, apoptosis, and cell differentiation, depending on the tissue type. There is still a knowledge gap regarding how cells undergoing WGD can overcome its deleterious effects and evolve into tumoral cells. Some laboratories in the field of chromosomal instability have recently explored this paradox and identified biomarkers that modulate polyploid cells to become oncogenic. This review provides a historical perspective on how WGD and polyploidy impact cell fitness and cancer progression and summarizes the latest studies describing genes that help cells adapt to polyploidy.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)