Two papers recently were published on the role of oncogene over expression, replication-stress and genomic instability. Overexpression of CCNE1 and MYC is frequently observed in triple-negative breast cancers. In a recent paper by Sergi Guerrero and colleagues in npj Breast Cancer, we show that CCNE1 and MYC levels are correlated with expression of gamma-H2AX and p-RPA, two markers of replication stress in a large cohort of breast cancer patients.
In related work, that was a joint effort by PhD students Yannick Kok, Sergi Guerrero Pepijn Schoon, under supervision by Nathalie van den Tempel and myself, and published in Oncogenesis, we show that CCNE1 is causally involved in inducing replication stalling, mitotic defects and genomic instability.
In a close collaboration of PhD student Anne Margriet Heijink with the lab of Michael Lee (U-mass, MA, USA), we studied the response to cisplatin. In triple-negative breast cancer models, we observed a large variety in the sensitivity to cisplatin, which we could not explain by DNA repair defects. Using a systems biology approach, we created a signaling map of the cellular response to cisplatin, and uncovered determinants of this response in triple-negative breast cancer cell lines. This work was published in Cell Reports.
Happy to be part of this fruitful collaboration with the lab of Arnab Ray Chaudhary, in which Rif1 was shown to be required for protection of stalled replication forks.
On Wednesday July 10th, Stephanie van Gijn Successfully defended her PhD thesis. Well done Stephanie and good luck in your new position at the University of Zurich!
The 5th lab retreat in the Czech Republic, with lab members from the labs of Arne Lindqvist (Karolinska, Stockholm), Libor Macurek (IMG, Prague), Vincenzo D’angiolella (Oxford University, Oxford) and Zuzana Horejsi (Barts Cancer Institute, London). Great talks, excellent beers, and constructive discussion!
Former PhD student Anne Margriet Heijink received a prestigous long-term EMBO fellowship to work in the lab of Dan Durocher in Toronto! very well done!!
Pepijn Schoonen successfully defended his PhD thesis on May 22nd! As can be seen on the picture, Pepijn was fully in control. Congrats Pepijn!
Anne Margriet Heijink and Francien Talens in collaboration with the Brummelkamp lab (NKI, Amsterdam) published their manuscript on how BRCA2 depleted cells instigate cGAS/STING-dependent interferon signaling in Nature Communications. This works shows how inflammatory signaling is induced by HR-defects, and makes tumor cells sensitive to TNFa-induced cell death.
Another successful lab retreat in the mountains of Czech Republic with the labs of Arne Lindqvist (Karolinska, Stockholm), Libor Macurek (IMG, Prague), Vincenzo D’angiolella (Oxford University, Oxford) and Zuzana Horejsi (Barts Cancer Institute, London)
Happy to be part of this collaborative paper on PARG loss as a mechanism of resistance to PARP inhibition! Congrats to Ewa Gogola and Sven Rottenberg
On April 10, the first Dutch Replication meeting was organised at the University of Delft. Nynke Dekker did a great job in organising a great meeting! As a bonus, post-doc Nathalie van den Tempel from our lab won the prize for best poster presentation!
On March 28th, Anne Margriet successfully defended her PhD thesis. Congratulations! well-deserved!
Glad to be part of this nice story by Walderik Zomerman and Sophia Bruggeman in Cell Reports.
Rolf de Boer did a great job in defending his PhD thesis on Wednesday December 13th. Congratulations dr. de Boer!
For her presentation at the annual meeting of the Dutch Society for Radiobiology, Anne Margriet won a Klaas Breur travel grant!
At the 5th annual PhD day of the Cancer Research Center Groningen (CRCG), Francien won the prize for best poster presentation. Congratulations!
Pepijn Schoonen’s manuscript on mitotic errors in response to PARP inhibitor treatment in HR-deficient cells has been published in Nature Communications. Using multiple models systems, we show that progression through mitosis facilitates cytotoxic effects of PARP inhibitor treatment, a phenomenon that could be exploited in combination therapies, and may also underlie effects of other chemotherapeutic treatments.
For the 3rd time, we organised a succesful lab retreat in the Czech Republic, together with labs of Arne Lindquist (Karolinska, Sweden), Gerben Vader (Max Planck, Germany) and Libor Macurek (University of Prague, Czech Republic).
For a research paper in J Cell Bio, in which a novel role of PGAM1 in controlling DNA repair is described, I wrote a spotlight article. the PGAM protein are essential regulators of glycolysis, and determine pentose-phosphate flux. This pathway controls biomass generation (including nucleotides) and is especially important for cancer cells. Genetic or chemical inhibition of PGAM1 blocks DNA repair and renders cancer cells sensitive to DNA damaging agents.
The paper of Stefanie Ruf (Kathrin Thedieck lab) appeared online in Autophagy. In this paper a novel role for Polo-like kinase-1 (PLK1) in controlling authophy was identified based on experiments in human cells and C. Elegans.
Rico Bense’s paper appeared online in the JNCI. Rico used bioinformatics analysis to identify the presence and activation status of immune cells in tumor samples, based on RNA expression data.
Colin Stok joined the lab as a PhD student. Colin Studies Life Sciences at Leiden University, and will work on the recently granted ERC project on DNA damage resolution during mitosis. Good luck!
the paper of Alina Fedoseinko (Bart van der Sluis’ lab) and Hylke Wieringa on COMMD1 and cisplatin sensitivity appeared in PLOS One. Congratulations!
Together with the research groups of Arne Lundqvist (Karolinska Institutet, Stockholm, Sweden), Libor Macurek (Institute for Molecular Genetics, Prague, Czech Republic), Gerben Vader (Max Planck Institute for Molecular Physiology, Dortmund, Germany), we organised a very succesfull second retreat in the Czech mountains.
The European Research Council awards an ERC Consolidator grant to our work on processing of DNA damage during mitosis, and the translation of these findings in clinical samples.
Two review papers from our group were published. Rolf de Boer and Sergi Guerrero Llobet published a review on how the APC/C-Cdh1 E3 ubiquitin ligase is controlled by DNA damage. This work was published in Cellular and Molecular Life Sciences.
Increasingly, Wee1 is considered a potentially valuable target in treating cancer. Unclear however is which tumor cells are most sensitive for Wee1 inhibitor treatment. Anne Margriet Heijink in our lab conducted an unbiased genetic screen in near-haploid KBM-7 cells, to uncover gene mutations that determine sensitivity to the Wee1 inhibitor MK-1775/AZD-1775. Surprisingly, several genes that function in the G1/S machinery were identified to determine Wee1 inhibitor sensitivity. These data were published in Proc. Natl. Acad. Sci. U.S.A.
In a collaboration with the group of Professor Susanne Lens (UMC Utrecht), we identified Rif1 as a factor that helps to resolve ultrafine anaphase bridges (UFBs). Phd students Rutger Hengeveld from Utrecht, and Rolf de Boer from our lab joined forces to show that Rif1 -which during interphase functions in repair of DNA breaks- adopts a new function during mitosis. Our findings were published in Developmental Cell.
Together with the research groups of Arne Lindqvist (Karolinska University, Stockholm) and Libor Macurek (Institute of Molecular Genetics, Prague), a successful retreat was organised close to the Jizera mountains in the Czech Republic.
The review by Malgosia Krajewska et al on how components of the HR DNA repair machinery can be utilised as targets for therapeutic intervention to promote the sensitivity of cancer cells to DNA damaging agents has been published in Frontiers of Genetics.
Post-doc Ines Teles Alves and I wrote an editorial in Cell Cycle on the exciting papers by the labs of Dan Durocher (Orthwein et al, Science, 2014) and Libor Macurek (Benada et al, Cell Cycle, 2015). In their papers, they demonstrate how mitotic kinases, notably Plk1, affect the DNA repair machinery to prevent DNA double strand break repair through non-homologousend-joining.
The cytogenetics analysis paper by Rudolf Fehrmann is online now in Nature Genetics. Together with the Department of Medical Genetics (Lude Franke), a ‘big data’ analysis was performed on publicly available mRNA expression profiles. This resulted in the discovery of a limited number of ‘transcriptional regulators (TCs)’. These TCs can be exploited to predict gene function, and were used to identify the Fen1 gene as a regulator of HR DNA repair. In addition, these TCs can be used to infer copy number variation in cancer samples, and allowed us to perform a GWAS analysis with genomic instability as a phenotype.
In close collaboration with the lab of Alex Sartori at the University of Zurich, we identified the DNA repair protein CtIP as a novel APC/C target. Our study is now published in the EMBO journal.
As a results of HR inactivation, tumor cells activate the replication checkpoint kinase ATR. Analysis of cancer samples revealed that high expression of the ATR gene was associated with genomic instability, and experimental work showed that HR-deficient cancer cell lines are more sensitive to chemical ATR inhibition, when compared to genomically stable cancer cell lines. This study by Malgosia Krajewska et al, is now published in Oncogene.
Malgosia Krajewska successfully defended her PhD thesis entitled: “Targeting Homologous Recombination in Cancer Cells” on June 30th 2014 at the University of Groningen.
The Dutch Cancer Society has granted a research project to Steven de Jong, Jourik Gietema and Marcel van Vugt, to study the underlying mechanisms that explain cisplatin sensitivity in testicular cancer. We are now looking for a highly motivated PhD student to work on this project.
In close collaboration with the Department of Gynecological Oncology, we have identified the DNA damage checkpoint gene CHK2 as a determinant of cisplatin response in high grade serous ovarian cancers. This work by Nicolette Alkema and colleagues was published in Gynecological Oncology this month.
The cellular response to DNA damage depends on the cell cycle status of these cells. During mitosis the response to DNA damage, and specifically DNA breaks, appears to be altered. Anne Margriet Heijink and Malgosia Krajewska have reviewed the current literature on this topic, which appeared in the Mutation Research journal.
On May 15th, Dutch Minister of health, Edith Schippers, was offered the final product of the young Health council of the Netherlands (www.2013.jonggrmagazine.nl). I was privileged to be part of the first committee, of which details are provided on Facebook. The presentation of the young Health Council to the Minister was covered in national newspapers and I wish the newcommittee all the best.
The activation status of Cdk1 appears to control the levels of HR repair in mammalian cells. PhD student Malgosia Krejewska’s paper was published in Oncogene, showing that elevation of Cdk1 activity leads to decreased ability to perform homologous recombination.
The amount of ATM activity, prior to radiotherapy, predicts loco-regional survival of advanced stage cervical cancer patients. MD-PhD student Hylke Wieringa (along with PhD student Frank Roossink) published their findings in the International Journal of Cancer