Recruitment

ESR 1: Netherlands Cancer Institute

A PhD candidate was recruited at the Netherlands Cancer Institute (NKI) in Amsterdam, the Netherlands. This position was filled by Mar Soto.

Project title: The relationship between structural and numerical chromosomal instability.

Reference: ESR 1/ NL

Description: The presence of an abnormal chromosome number is a hallmark of most human malignancies. This aneuploid karyotype is usually accompanied by continuous gains and losses of chromosomes upon erroneous cell divisions, a feature referred to as chromosomal instability (CIN). We have recently uncovered that errors in chromosome segregation can lead to DNA breaks and subsequent translocations and that enhancing chromosome segregation errors can compromise the viability of tumor cells. In this project we aim to understand: i) how missegregating chromosomes are damaged after a failed segregation event and ii) how CIN can be exploited in anti-cancer treatments. We will execute these studies both in tissue culture as well as in mice.

We seek a highly motivated, independent and creative individual. Candidates with a strong background and working experience in cancer biology, cell biology, imaging/microscopy and/or animal models are encouraged to apply. The working language at the Netherlands Cancer Institute is English.

Main objectives project

  • Determine relationship between structural and numerical chromosomal instability (CIN).
  • Develop tools to determine chromosome damage as a result of chromosomal instability (CIN).
  • Assess feasibility of Mps1 inhibitors for cancer therapy.
  • Location: Netherlands Cancer Institute, Amsterdam, the Netherlands.

Supervisor: René Medema
Length of appointment: 36 months (3 years)
Indicative Starting date: June 2014

Important!! Please read the eligibility requirements (see under “Eligibility“) to make sure that you are eligible for the position before you apply!

Application: eligible candidates should fill in the application form and upload a cover letterstating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document through the contact form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.
Hours per week: 36


ESR 2: ERIBA/UMCG

A PhD candidate was recruited at the European Research Institute for the Biology of Ageing/ University Medical Center Groningen, the Netherlands. This position was filled by Klaske Schukken.

Project title: Mouse models to monitor chromosome segregation in aneuploid tumours by intravital imaging.

Reference: ESR 2/ NL

Description: Aneuploidy, an abnormal number of chromosomes, is a hallmark of cancer cells. Paradoxically, aneuploidy is poorly tolerated by normal cells in tissue culture, suggesting that cancer cells employ mechanism to cope with the otherwise detrimental consequences of aneuploidy. We recently found that aneuploidy is remarkably well tolerated by the basal cells in mouse epidermis, whereas stem cells in the same tissue succumbed due to aneuploidy. This suggests that different cell lineages cope differently with chromosomal instability emphasizing the importance of in vivo modeling. In this project, the PhD student will engineer mouse models to monitor chromosome segregation in vivo, which will be combined with our existing models for aneuploidy in the skin to allow us to monitor the consequences of aneuploidy real-time in an unperturbed tissue. Furthermore, this student will closely collaborate with ESR3 developing in vivo probes for spindle assembly checkpoint activity.

Main objectives project:

– Develop various reporters for mitosis in ES cells and test feasibility by time-lapse imaging

– Develop mitotic reporter mice strains with and without conditional SAC alleles

– Measure chromosome mis(segregation) using intravital imaging and in 3D culture conditions

Location: ERIBA/ University Medical Center Groningen, the Netherlands.

Supervisor: Floris Foijer

Length of appointment: 36 months (3 years)

Indicative Starting date: October 2014

Important!! Please read the eligibility requirements (see under “Eligibility“) to make sure that you are eligible for the position before you apply!

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document through the contact form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


ESR 3: University of Utrecht 

A PhD candidate was recruited at the University of Utrecht in the Netherlands. This position was filled by Ana Bolhaqueiro.

Reference: ESR 3/ NL

Project Title: A biosensor for mitotic spindle checkpoint activity in vitro and in vivo to study mitotic processes in 3D organoid cultures

Description: The PloidyNet project in the Kops lab will revolve around examining function of various mitotic processes in real time in 2D and 3D cell cultures of normal and aneuploid cells and organoids. Questions that we would like to answer, are: Does spindle assembly checkpoint activity correlate with fidelity of chromosome segregation in aneuploid cells/organoids? Does attachment error-correction? Do specific chromosomes have an elevated tendency for missegregation in cancers? The study will involve development and imaging of biosensors for these mitotic processes, as well as genome editing strategies to examine specifics of chromosome behavior during mitosis. Healthy and cancerous organoids will be grown from tissues of several chromosomally unstable mouse strains, and this will be extended to human cancer organoids.

Objectives

–        Develop mouse reporter for Cyclin B activity

–        Measure SAC activity in vivo and in organoid cultures

–        Measure Cyclin B activity in Mad2 overexpressing mice

–        Develop mitotic biosensors for live cell imaging

–        Use biosensors to analyse funcion of mitotic processes in cell lines

–        Examine chromosome segregation and mitotic processes in healthy and cancer organoids of mice and humans

Location: University Utrecht, Utrecht, the Netherlands.

Supervisor: Geert Kops

Length of appointment: 36 months (3 years)

Indicative Starting date: June 2014

Application:  eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas (day, month and year), and the contact information of 2 referee persons, all as a single pdf document through the contact form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36. 


ESR 4 University of Manchester : 

A PhD candidate was recruited at the University of Manchester, in the UK. This position was filled by Susana Sousa.

Reference: ESR 4/ UK

Project Title: Development of biosensors to define how aneuploidy triggers a stress response

Description: In non-transformed cells, aneuploidy has a negative impact on proliferation. Yet cancer cells proliferate efficiently despite continuously missegregating their chromosomes. This suggests that cancer cells acquire the ability to tolerate aneuploidy. We have identified a MAP kinase “stress response” pathway which is activated following chromosome missegregation. In turn this activates a p53-dependent post-mitotic checkpoint which restrains cell cycle progression of aneuploid cells. The PloidyNet project in the Taylor lab will develop p53 biosensors to quantify the output of post-mitotic aneuploidy responses in living cells. The upstream MAP kinase pathway will then be modulated using a variety of modalities including RNAi, dominant negative mutants and small molecule inhibitors, and the effects on p53 induction measured. Aneuploid cells that bypass the p53 response will be expanded and analysed by state-of-the-art karyotyping techniques to determine whether all chromosomes are equally missegregated, and to determine whether aneuploidy can trigger chromosome instability, a hallmark of cancer.

Objectives:

– Develop human and mouse biosensors for p53 induction.
– Monitor p53 induction following aneuploidy induction in cell culture.
– Modulate the p38 pathway and determine the impact on p53 induction.
– Develop & characterise aneuploid cell lines by bypassing the stress response pathway.
– Characterise aneuploid clones, e.g. state-of-the-art karyotyping, time-lapse microscopy.

Location: University of Manchester, Manchester, UK.

Supervisor: Stephen Taylor

Length of appointment: 36 months (3 years)

Indicative Starting date: June 2014
Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form herunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


 

ESR 5 University of Edinburgh : 

A PhD candidate was recruited at the Welcome Trust Centre for Cell Biology, University of Edinburgh, in the UK. This position was filled by Jan Ruppert.

Reference: ESR 5/ UK

Project Title: Using HACs to study the effects of aneuploidy-inducing drugs on kinetochore composition (WP4, WP5)

Description: This project will begin with the construction of synthetic human artificial chromosomes (HACs) in non-transformed cell lines and in transformed cell lines with varying degrees of chromosomal instability (CIN) phenotype (collaboration with Zuzana Storchova – Partner 7 in this ITN). These synthetic HAC-containing cell lines will be used to study the effects of various drugs and perturbations of the epigenetic status of centromeric chromatin on chromosome segregation and aneuploidy. The student will design and construct specific chromatin modifiers and purification tags that target to the synthetic alpha-satellite DNA of the HAC centromere. As one example, this system will allow the student to determine the effect of particular drugs on the segregation of the HAC with stronger or weaker heterochromatin in the centromere – sensitized screens that are not possible with current technology. An alternative approach will be for the student to attempt to isolate the HAC in amounts sufficient to perform a proteomic analysis of its components. If it is possible to isolate the HAC in sufficient amounts, the student will use selected reaction monitoring (SRM) proteomics in the lab of Erich Nigg (Partner 6) to characterise the HAC proteome. In parallel with this work on synthetic HACs, the student will also explore use of a “top-down” approach to try and isolate a novel HAC based on a non-repeated underlying centromere DNA sequence. This will be done by excising a neocentromere fragment from a human cell line and also by attempting to stabilize a centromere-containing fragment from the chicken Z chromosome in human cells. Such HACs with  non-repeated centromeric DNA sequences can be completely sequenced and mapped and are therefore potential vectors for future gene therapy projects.

Objectives:
– Develop tools that can be used to screen for compounds that cause CIN

– Assess the value of HACs as a tool to study CIN

– Determine kinetochore composition on missegregated chromosomes

Location: The University of Edinburgh, Edinburgh, the UK.

Supervisor: Bill Earnshaw

Length of appointment: 36 months (3 years)

Indicative Starting date: 1 September 2014

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


ESR 6 University of Edinburgh : 

A PhD candidate was recruited at the University of Basel in Switzerland. This position was filled by Cristina Viganó.

Reference: ESR 6/ CH

Project Title: Quantitative measurements of mitotic complexes in aneuploid and euploid cells.

Description: The fellow will be performing her/his thesis work at the Biozentrum, University of Basel, under the supervision of Prof. Erich Nigg.
The project aims at understanding the mechanisms underlying chromosome segregation during cell division, with emphasis on chromosomal instability that characterizes human tumour cells. The Nigg laboratory works primarily with human cells in culture and uses biochemical methods as well as cell and molecular biology approaches. Mass spectrometry is a key method for investigating protein complexes, while high resolution microscopy is used to study living cells.
We seek a highly motivated, well-trained and independent individual with a specific interest in mitotic chromosome segregation. Candidates with a strong background and working experience in cell/molecular biology, biochemistry and microscopy and/or proteomics are encouraged to apply. The successful applicant will work in an outstanding and international research environment. The working language is English.

Objectives:

– Develop SRM-based proteomics further for mitotic complex measurements

– Measure the abundance and the stoichiometry of selected protein complexes at any given stage of mitotic progression

– Measure the key regulatory protein complexes in cells displaying various levels of aneuploidy

Location: University of Basel, Basel, Swizerland.

Supervisor: Erich Nigg

Length of appointment: 36 months (3 years)

Indicative Starting date: February 2014 – June 2014, decided upon mutual agreement.

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form below.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


 

ESR 7 Max Planck Institute :

A PhD candidate was recruited at the Max Planck Institute of Biochemistry in Martinsried, Germany. This position was filled by Katarzyna Seget.

Reference: ESR 7/ DE

Project Title: Identification of genes that mediate a p53-regulated arrest in response to aneuploidy.

Description: Aneuploidy arises from missegregation of chromosomes during mitosis; however, most of the human cells die after chromosome missegregation. In order to understand the mechanisms which determine survival of aneuploid cells, we will identify the triggers of the p53 dependent cell cycle arrest that follows after chromosome missegregation in most human cells and the mechanisms that enable to escape this fate. We have recently finished high-throughput screen to determine genes that affect proliferation of cells after abnormal mitosis. To verify the results and to uncover the involved mechanisms, we will knock down promising candidates either in chromosomally unstable cancer cell lines or in our recently established model of human aneuploid cells with defined karyotype changes. Using live cell imaging, we will then analyze the fate of these cells. After identifications of pathways required for survival of aneuploid and chromosomally unstable cells, we will test known inhibitors of these pathways for selective killing of chromosomally unstable cancer cell lines. These experiments will directly address the mechanisms by which aneuploidy triggers the cell cycle delay or cell cycle arrest and may open a novel window of opportunities for cancer treatment.

Objectives:
– Identify genes that orchestrate the p53 response in response to CIN

– Determine the role of the DNA damage response following CIN

Location: Ludwig Maximiliaan University Munich, Germany.

Supervisor: Zuzana Storchova

Length of appointment: 36 months (3 years)

Indicative Starting date: June 2014

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


 

ESR 8 EMBL :

A PhD candidate was recruited at the European Molecular Biology Laboratoty (EMBL), in Heidelberg, Germany. This position was filled by Sharavan Venkateswaran.

Reference: ESR 8/ DE

Project Title: Grading CIN in the mammary gland: the in vivo consequences of aneuploidy

Description: Overexpression of the mitotic checkpoint protein Mad2 cooperates with mutant Kras to accelerate lung cancer and facilitates tumour relapse after targeted therapies. We recently found that high Mad2 levels are badly tolerated by mammary epithelial cells. This suggests that lung and mammary epithelial cells respond differently to SAC hyperactivation. The student will use in vitro 3D cultures of primary epithelial cells and in vivo mouse models, to analyze the role of different levels of SAC activation in tumour development. In addition, he/she will collaborate with ESR2 to study the consequences of Mad2 inactivation in the mammary gland. The student will spend 1 year at EMBL (Italy) and then move to the DKFZ in Heidelberg, Germany.

Objectives:
– Compare the consequences of SAC inactivation and hyperactivation for mammary tumourigenesis in predisposed models

– Determine the molecular consequences of CIN in murine mammary tumours

– Measure the earliest measurable consequences of SAC abnormalities in the mammary gland

Location: DKFZ, University of Heidelberg, Heidelberg, Germany.

Supervisor: Rocio Sotillo

Length of appointment: 36 months (3 years)

Indicative Starting date: June 2014

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form herunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


 

ESR 9 LRI :

A PhD candidate was recruited at the London Research Institute in the UK. This position was filled by Thomas Watkins.

Reference: ESR 9/ UK

Project Title: Defining a mechanistic basis for chromosomal instability in NSCLC

Description: Non-small cell lung cancer (NSCLC) is characterised by late presentation and dismal overall survival. Intratumour genetic and functional heterogeneity has previously been described in NSCLC with evidence supporting the relationship between intratumour heterogeneity (ITH) and poor outcome. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) is a prospective cohort study of patients with primary NSCLC, which through multi-region and longitudinal tumour analysis, aims to define the evolutionary trajectories of lung cancer in both space and time in relation to selection pressures such as cancer therapies. The focus of this project would be to use bioinformatics approaches to identify branched evolutionary events and cancer mutational signatures in NSCLC that may determine increased risk of recurrence and somatic events that promote or sustain on-going cancer genome instability. The candidate would be expected to either be interested in wet lab work or collaborate with wet laboratory teams in the group to derive cell lines from TRACERx samples ex vivo from heterogeneous tumours in order to monitor tumour aneuploidy in vitro. The student will also use the p21 and p53 reporters developed in Stephen Taylor’s lab as biosensors in human cell lines. The student will aim to combining bioinformatics analysis of heterogeneous genomically unstable lung cancers with ex vivo derived cell cultures defined by aneuploidy status to define key drivers of tumour aneuploidy initiation and tolerance in vivo.

Objectives:
– Identify the drivers of aneuploid lung cancer

– Assess the contribution of the DNA damage response to the biology of aneuploid lung cancers

– Develop tools to quickly screen for DNA damage pathway activity in primary tumour cells

Location: University College London, London, UK.

Supervisor: Charles Swanton

Length of appointment: 36 months (3 years)

Indicative Starting date: September 2014

Application: eligible candidates should fill in the application form and upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document into the form hereunder.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36


ER 1 NTRC :

A Postdoc position was available at the Netherlands Translational Research Center B.V. ( NTRC) in Oss, the Netherlands. The recruitment is currently in progress, the vacancy has been closed.

Reference: ER 1/ NL

Project Title: Optimization of aneuploidy-modulating drugs.

Description: The protein kinase TTK (Mps1) plays a critical role in the mitotic checkpoint. Inhibition of TTK causes chromosome missegregation, resulting in apoptosis. NTRC has developed a series of small molecule inhibitors of TTK. Compounds are highly selective and potent inhibitors of cell proliferation. Crystal structures of TTK in complex with inhibitors have been resolved at NTRC and are available to guide the design of new inhibitors. The ER will synthesize and optimize novel TTK inhibitors and design and synthesize inhibitors of other kinases involved in aneuploidy. The inhibitors will be profiled in biochemical and cellular assays and tested in combination with other chemotherapeutic agents. Once optimized, tested in animal models available at academic collaborators in the project.

Objectives:
– Determination of the clinical value of TTK inhibition in mouse models using small molecule compounds.

– Design and synthesis of novel inhibitors of aneuploidy-modulating enzymes.

Location: Oss, The Netherlands

Supervisor: Rogier Buijsman

Length of appointment: 24 months (2 years)

Indicative Starting date: March 2015

Application: eligible candidates should upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document. Applicants should have ample experience in medicinal chemistry.

Type of Contract: temporary.

Hours per week: 40


ER 2 Miltenyi Biotech :

A Postdoctoral fellow was recruited at Miltenyi Biotech Inc. in Bergisch Gladbach, Germany. This position was filled by Patrícia Domingues.

Reference: ER 2/ DE

Project Title: The relationship between genetic instability and cellular phenotypes on the protein level.

Description: The overall aim of this project is to develop novel methods for the isolation and analysis of aneuploid cells. A central task will be the identification of biomarkers, with a focus on cell surface markers, which link the aneuploidy of a cell to its phenotype. More specific, the relationship between aneuploidy and cellular heterogeneity in cancer tissues will be analyzed. The cancer stem cell model proposes a hierarchical organization in tumors similar to that of normal tissues. Therefore, a further goal would be to evaluate how distinct cell subpopulations like dormant stem cells handle aneuploidy in contrast to fast dividing progenitor or more differentiated populations.
To address these questions, methods for the identification and isolation of tumor resident subpopulations will be established. Purified cells will then be characterized on the molecular and functional level. Next to the analysis of co-existing cell populations, the relation of aneuploidy and pathways central for tumor progression, like Epithelial-to-Mesenchymal transition, will be evaluated.

Objectives:
– Identify (cell surface) markers that are correlate with aneuploid genome content

– Develop a flow cytometry-based protocol to measure tumour heterogeneity

– Determine response to CIN in various sub-populations of cells using flow cytometry.

Eligibility (who can apply): Experienced Researchers (ER).
Eligibility will be checked based on the following cumulative criteria:
a) Applicants Career Stage: Only Experienced Researchers (ER) should apply, that is, researchers who, at the time of recruitment by the partner of Ploidynet are [1] in possession of a doctoral degree or have at least 4 years of full-time equivalent research experience, and [2] have less than 5 years of full-time equivalent research experience.
b) Mobility: At the time of recruitment, the researcher must not have resided or carried out his/her main activity (work, studies, etc.) in the country of the partner of Ploidynet he/she is applying for, for more than 12 months in the 3 years immediately prior to the his/her recruitment under the project. Compulsory national service and/or short stays such as holidays are not taken into account.
IMPORTANTE NOTE: the career stage of eligible applicants and the mobility rule is determined in terms of full-time research equivalent years. This means that research experience is measured from the date when a researcher obtained the degree which would formally entitle him/her to embark in a PhD degree, either in the country in which the degree was obtained or in the country in which the researcher is recruited, irrespective of whether or not a PhD degree is or was ever envisaged.

Location: Myltenyi Biotec, Cologne, Germany.

Supervisor: Olaf Thorsten Hardt

Length of appointment: 15 months

Indicative Starting date: Dec 2014

Application: eligible candidates should upload a cover letter stating their motivation and research interests, an updated CV with the dates of relevant diplomas ( day, month and year), and the contact information of 2 referee persons, all as a single pdf document.

Applicants should apply to their preferred research team within PloidyNet’s network, but they can indicate a secondary preference in their application.

Type of Contract: temporary.

Hours per week: 36