This 4 year PhD studentship offered in Dr Maximiliano Portal’s research group is based at the Cancer Research UK Manchester Institute, Alderley Park, Cheshire
Recent discoveries led by the development of single-cell technologies revealed that cellular populations are indeed quite heterogeneous (1-3). Intriguingly, this variability cannot be solely explained by genetic differences, but rather suggests that biological information may be also encoded in alternative molecular devices other than DNA (Darwin’s Pangenesis) (4). An illustrative example of this can be readily seen during cancer development; where transformed cells are constantly exposed to changing conditions within their niche of origin and further within the ecosystems encountered whilst invading novel tissues (5,6). This fast-paced environment drives a micro-evolutionary process that gives rise to distinct sub-clones within a tumour, ultimately leading to increased heterogeneity along the course of the disease. Importantly, this variability can either arise as a result of somatic mutations acquired during tumour development or may be established due to the ability of a single genotype to produce many discrete, sometimes dramatically different, phenotypes. In our lab we believe that biological systems based on the latter will enable us to study the molecular basis underlying non-genetic information generation and inheritance whilst also giving us the opportunity to explore the mechanisms underlying anti-cancer drug resistance from a unique perspective.
In that view, we have recently developed a battery of oncogene-induced transformation models to study the mechanisms underlying the inheritance of non-genetically encoded traits. Our models are based on the drug-induced activation of a cell death pathway, which results in apoptosis whilst concomitantly generating a resistant subpopulation. Notably, the resistant subpopulation resumes growth in the presence of the drug and regains sensitivity following its withdrawal. However, this only occurs after a defined number of cell divisions, 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” drug-resistant phenotype makes these systems an ideal experimental choice to pinpoint non-genetic information carriers and to explore their relevance in the establishment and/or propagation of epigenetic heterogeneity.
The main objective of this PhD project is to further develop single-cell technologies custom-built in the lab with the ultimate aim to untangle the contribution of non-genetic events from classical genetics during tumour development or throughout the emergence of drug resistance. In particular, the student will explore dynamic changes in the expression, intracellular localization and segregation of coding/non-coding RNAs and its link with epigenetic events to explore the underlying basis of epigenetic heterogeneity in isogenic cancer model systems.
The successful candidate will benefit extensively from training in molecular and cellular biology, cancer cell biology, epigenetics, non-coding RNA biology and bioinformatics. 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.
Applications are invited from exceptionally high calibre students, graduates or final year undergraduates who should hold or are expected to gain a first/upper second-class honours degree in a relevant subject as part of a University degree course.
Applicants can find full group project details, entry criteria and details on how to apply online at: http://www.cruk.manchester.ac.uk/education/PhD-Studentships
Closing date: Friday 3 January 2020 – 2100 hours GMT
Interview date: Tuesday 18 February 2020, Alderley Park, Cheshire
1. Chang, H., Hemberg, M., Barahona, M., Ingber, D.E. & Huang, S. Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453, 544-547 (2008).
2. Altschuler, S.J. & Wu, L.F. Cellular heterogeneity: do differences make a difference? Cell 141, 559-563 (2010).
3. Shlyakhtina, Y., Moran, K.L. & Portal, M.M. Asymmetric Inheritance of Cell Fate Determinants: Focus on RNA. Noncoding RNA 5 (2019).
4. Zhang, Y. & Chen, Q. The expanding repertoire of hereditary information carriers. Development 146 (2019).
5. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57-70 (2000).
6. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi:10.1016/j.cell.2011.02.013 (2011).