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PhD Scholarships

4 Year CRUK PhD Studentship – September 2018 Genesis and Propagation of Epigenetic States…

*4 Year CRUK PhD Studentship – September 2018*
_*“Genesis and Propagation of Epigenetic States Underlying Drug Tolerance”*_

*Cell Plasticity and Epigenetics Research Group – Dr Maximiliano Portal*

It is generally accepted that tumours are subjected to a myriad of evolutionary constraints at their niche of origin and further within the ecosystems encountered while invading novel tissues1,2. Thus, evolutionary forces shape cancer development on many levels, as progression of the disease is often correlated with the appearance of somatic mutations and the selection of genetic traits that eventually become beneficial to neoplastic growth and often prejudicial to the host. Indeed, often-acquired mutations alter growth control systems and obliterate cell death programs, ultimately granting mutated cells with replicative immortality at the expense of genetic instability. However, due to the variable nature of the selective pressure in a particular niche, stable somatic mutations arise only after recurrent encounters with a challenging force. This suggests that, though under heavy evolutionary constraints, genetic changes driving adaptation do not occur immediately and highlights the biological relevance of cancer cell plasticity during neoplastic evolution3.

A striking example that brings forward the plasticity of cancer cells is their resilience when confronted with therapeutic paradigms. Indeed it is acknowledged that, in response to sustained treatment, cancer cells may acquire genetic mutations that permanently block the tumouricidal action of the administered drug. However, in other settings, the emergence of fully drug-resistant clones cannot be explained by genetic mechanisms and results from cells that escape the initial death challenge by “adapting” to the pernicious agent. In the latter scenario, the traits granting adaptation to treatment are reversible in nature and are readily inherited through several cell divisions. This particularity strongly suggests the existence of a non-genetically encoded “temporal memory” underlying the acquisition of “drug-tolerant” phenotypes and represents an exquisite example of the transfer of non-genetic information through cell division4-6.

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Under this premises, we have developed a solid cellular model to study the mechanisms underlying the inheritance of non-genetically encoded “drug-resistant” states. Our model is based on the drug-induced activation of a cell death pathway, which in several cancer-derived cell lines prompts cell death while concomitantly generates a resistant subpopulation. Notably, the resistant subpopulation resume growth in the presence of the death-triggering agent and following the removal of the drug, regain drug-sensitivity but only after a defined number of cell divisions. Thus suggesting that the drug-tolerant phenotype is sustained by cell plasticity rather than driven by stable genetic changes. The short-lived, dynamic and reversible nature of the “induced resistant phenotype” makes this system the ideal choice to study epigenetic inheritance.

The main objective of this PhD project is to further explore/establish an experimental/computational framework to study epigenetic inheritance in cancer relevant settings. In particular, the student will generate from a single non-transformed “parental” cell line a battery of cellular models were the introduction of oncogenic factors (H-RAS(G12V), BRAF(V600E) or MYC) drive cellular transformation. These cell lines will be used to analyze the generation and propagation of the innate/acquired resistant phenotype at a single cell level. In particular, we will explore dynamic changes in the expression, intracellular localization and segregation of non-coding RNAs and its link with epigenetic events supporting drug resistance7-12.
The successful candidate will benefit extensively from training in molecular and cellular biology, cancer cell biology, epigenetics and non-coding RNA biology. The student is expected to generate new biological insights into the mechanism underlying epigenetic information transfer through cell division and its potential role on the acquisition of drug resistance in cancer settings.

1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
2. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi:10.1016/j.cell.2011.02.013 (2011).
3. Trerotola, M., Relli, V., Simeone, P. & Alberti, S. Epigenetic inheritance and the missing heritability. Hum Genomics 9, 17, doi:10.1186/s40246-015-0041-3 (2015).
4. Brock, A., Chang, H. & Huang, S. Non-genetic heterogeneity–a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet 10, 336-342, doi:10.1038/nrg2556 (2009).
5. Pisco, A. O. et al. Non-Darwinian dynamics in therapy-induced cancer drug resistance. Nat Commun 4, 2467, doi:10.1038/ncomms3467 (2013).
6. Pisco, A. O. & Huang, S. Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me’. Br J Cancer 112, 1725-1732, doi:10.1038/bjc.2015.146 (2015).
7. Chandler, V. & Alleman, M. Paramutation: epigenetic instructions passed across generations. Genetics 178, 1839-1844 (2008).
8. Chandler, V. L. & Stam, M. Chromatin conversations: mechanisms and implications of paramutation. Nat Rev Genet 5, 532-544, doi:10.1038/nrg1378 (2004).
9. Suter, C. M. & Martin, D. I. Paramutation: the tip of an epigenetic iceberg? Trends Genet 26, 9-14, doi:10.1016/j.tig.2009.11.003 (2010).
10. Macara, I. G. & Mili, S. Polarity and differential inheritance–universal attributes of life? Cell 135, 801-812, doi:10.1016/j.cell.2008.11.006 (2008).
11. Lambert, J. D. & Nagy, L. M. Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature 420, 682-686, doi:10.1038/nature01241 (2002).
12. Xie, J., Wooten, M., Tran, V. & Chen, X. Breaking Symmetry – Asymmetric Histone Inheritance in Stem Cells. Trends Cell Biol 27, 527-540, doi:10.1016/j.tcb.2017.02.001 (2017).

Informal enquiries should be addressed to Dr Maximiliano Portal; [email protected]

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Interested students can find full group project details, entry criteria and details on how to apply on the CRUK Manchester Institute website;

*Closing date: Friday 19 January 2018, 2400 hrs (GMT)*
*Interview date: Wednesday 14 February 2018, Alderley Park, Cheshire*

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PhD Scholarships

PhD positions at The University of Warwick : Biological Sciences/Synthetic biology (# of pos: 4)

Our group is offering PhD positions for 2018-2019 academic year.  These studentships are hosted by The University of Warwick Doctoral Training Centres 

 Details below

1) PhD project title: Engineering microbial chemical factories to produce renewable and modified biomaterials. 

PhD is hosted via MIBT Partnership

Research Area  : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

2) PhD project title: Development of novel halogenase enzymes for biopharmaceutical applications.

PhD is hosted via MIBT Partnership

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

3) PhD project title: Expanding the genetic lexicon: Developing novel tools for non-natural amino acid incorporation in to therapeutic peptides and proteins.

PhD is hosted via SynBIO DTC 

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

4) PhD project title:  Bioplastics from E. coli

PhD is hosted via SynBIO DTC

Research Area : Synthetic biology, Organocatalysis, Structural biology and enzymology

Link :-

Applications are encouraged from UK, EU and International students.

Please be aware that International (non EU) applicants are not eligible for EPSRC/BBSRC funded studentships.

To be eligible for a full EPSRC/BBSRC award (Tuition fees and Stipend) a student must have:

  • Settled status in the UK, meaning they have no restrictions on how long then can stay and
  • Been ‘ordinarily resident’ in the UK for 3 years prior to the start of the studentship. This means they must have been normally residing in the UK (apart from temporary or occasional absences) and
  • Not been residing in the UK wholly or mainly for the purpose of full-time education. (This does not apply to UK or EU nationals).
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To be eligible for an EPSRC/BBSRC tuition fees only award:

  • Students from EU countries other than the UK are generally eligible for a fees-only award. To be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU, in the same way as UK students must be ordinarily resident in the UK.

Interested students with research experience and qualification please contact us directly.

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France Scholarships

PhD position in quantum optimal control theory at the University of Bourgogne

This PhD project aims at applying innovative mathematical tools coming

from optimal control theory to improve theoretical and experimental techniques

in Nuclear Magnetic Resonance (NMR), in Electron Spin Resonance (ESR) and in NV

centers. This approach will allow us to explore and to experimentally reach the

physical limits of the corresponding spin dynamics in presence of typical

experimental imperfections and limitations. A first objective will be to

develop new optimal control algorithms able for an inhomogeneous ensemble of

spins to maximize the signal to noise ratio per unit time of the system. A

general problem is to generalize the Ernst angle solution used in NMR, which is

only valid for a homogeneous spin ensemble. This work will be done in

collaboration with the group of S. Glaser (TUM, Munich, Germany). This approach

will find different applications in NMR and ESR where the sensitivity of the

experiment is a crucial parameter. The student will focus on a specific

experimental setup in ESR used by the group of P. Bertet (CEA, Paris Saclay),

where an important goal is the maximization of the emitted signal of spins

coupled to a microwave resonator. The student will take into account in the

numerical computation specific constraints of this experimental setup. In the

same direction, the student will also use optimal control techniques to design

new CMPG sequences accounting for the coupling between the spins and the

cavity. The same types of control techniques will also be used for manipulating

NV ensembles in collaboration with the group of T. Debuisschert (Thalès,

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Paris). This will allow the improvement of the sensitivity of the corresponding

experiments. For a more fundamental point of view, the ESR will investigate the

numerical techniques used to design robust control fields with respect to

experimental imperfections. A first objective will be to understand the

efficiency of these methods and to prove the optimality (this concept will be

to define rigorously) of the control fields. The ESR will mainly study spin

systems but it is clear that the results of this project will not be restricted

to the physical systems investigated and the techniques developed during the

PhD could be applied to other physical systems with similar properties.

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Israel Scholarships

Marie Curie Innovative Training Network (ITN) META-CAN – PhD position in Computational biology to…

The Machine Learning for Healthcare and Life Sciences group at IBM Research – Haifa is a partner in the funded Marie Curie Innovative Training Network (ITN) META-CAN. The network is a pan-European interdisciplinary and intersectoral training programme for excellence.  It brings young researchers together with world-leading academics, clinicians, and industry personnel to focus on the connections of metabolism, immune response, and cancer.

We are looking for an enthusiastic and highly-motivated early stage researcher (ESR), with a background and experience in computational biology, machine learning and/or statistics and good programming skills (preferably in Python or R). This ESR will study towards a PhD degree and, under our guidance (and in collaboration with the Technion Integrated Cancer Center), will analyze comprehensive omics data to better understand the metabolic adaptations of cancer cells to the central nervous system niche.

The right candidate will enjoy a competitive salary and outstanding work environment.

For more details see  or contact [email protected]

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