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Single-cell transcriptomics linked to lineage tracing to interrogate the role of 'plasticity first' as a positive force driving paediatric cancer evolution


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  Dr Alejandra Bruna, Prof L Chesler  No more applications being accepted  Funded PhD Project (Students Worldwide)

London United Kingdom Biochemistry Cancer Biology Cell Biology Molecular Biology

About the Project

Project Description 

The main goal of this project is to build a comprehensive temporal evolutionary picture, at single cell resolution, to define how paediatric solid cancer evolves during the formation of tumours and in response to both chemo- and targeted therapy. To this end, we will use state-of-the-art technological approaches and robust preclinical models, including genetically engineered mouse models (GEMMs) and patient-derived organoids, to creatively study clonal relationships and how these influence drug responses and evolutionary trajectories.

Children’s cancers are developmentally imprinted, and cell phenotypic switches or cell plasticity is a fundamental mechanism that governs development. We hypothesize cell plasticity/phenotypic switching is a positive cancer evolutionary force, which is especially relevant in children’s cancer (developmentally imprinted) and may allow prediction of treatment resistance.

However, a role of cell plasticity “first” as a positive driver of evolution has long been debated over centuries but supported only by little empirical evidence due to technological and experimental limitations.

In the Bruna lab, we aim to gain a better understanding on the evolutionary principles, laws and mechanisms that drive the deadliest of children’s cancer processes such as treatment resistance, recurrence and relapse. To this end, we use state of the art single-cell technologies and improved preclinical models to study and experimentally validate the role of phenotypic plasticity in adaptative evolution and genetic diversification. We aim to translate our evolutionary knowledge into improved treatment strategies which could turn into superior therapeutic responses, and these could more easily be anticipated. Moreover, our evidence on non-genetic evolutionary forces will be raising provocative questions regarding the long-term efficacy of targeted therapies instigating further investigations towards innovative treatments designed on combinations including a targeted compound plus inhibitors a compound that would disable the molecular mechanisms mediating cancer cell adaptation.

Keywords

  • Cancer Therapy
  • Paediatric cancer
  • Cell phenotypic plasticity
  • Single cell RNA-sequencing
  • Lineage tracing
  • Patient derived tumour models

Candidate profile

Candidates must have a First class or Upper Second class BSc Honours/MSc in a relevant subject area.

How to apply

To view the full project proposal and details on how to apply using our online recruitment portal, please go to icr.ac.uk/phds. Please ensure that you read and follow the application instructions very carefully.

Please note we only accept applications via the online application system apply.icr.ac.uk.

Applications close at 11:55pm UK time on 14 November 2021.


Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK and EU/overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world. We particularly welcome applicants from British Black and ethnic minority backgrounds, as they are under-represented at PhD level within the ICR and nationwide.

References

- Nowell PC. The clonal evolution of tumor cell populations. Science (80- ) 1976; 194: 23 LP – 28.
- Martincorena I, Raine KM, Gerstung M, et al. Universal Patterns of Selection in Cancer and Somatic Tissues. Cell 2017; 171: 1029-1041.e21.
- Turajlic S, Sottoriva A, Graham T, Swanton C. Resolving genetic heterogeneity in cancer. Nat Rev Genet 2019; 20: 404–16.
- Gröbner SN, Worst BC, Weischenfeldt J, et al. The landscape of genomic alterations across childhood cancers. Nature 2018; 555: 321.
- Morrissy AS, Garzia L, Shih DJH, et al. Divergent clonal selection dominates medulloblastoma at recurrence. Nature 2016; 529: 351–7.
- Schramm A, Köster J, Assenov Y, et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 2015; 47: 872–7.
- Karlsson J, Valind A, Holmquist Mengelbier L, et al. Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer. Nat Genet 2018; 50: 944–50.
Andersson N, Bakker B, Karlsson J, et al. Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers. Cancer Res 2020; : canres.3468.2019.
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