Understanding interplay between genetic intra-tumour heterogeneity and the local tumour microenvironment
Dr E Sahai
Tuesday, November 12, 2019
Funded PhD Project (Students Worldwide)
This 4-year PhD studentship is offered in Dr Erik Sahai’s Group based at the Francis Crick Institute (the Crick).
Intra-tumour heterogeneity represents a major challenge in the treatment of cancers. This heterogeneity can be genetic, that is mutations only present in a subset of cancer cells, or in the composition of the tumour microenvironment, the non-cancerous cells and matrix within a tumour. The relationship between genetic heterogeneity within a tumour and the microenvironment is crucial to ongoing tumour evolution and the ultimate success or failure of therapies, yet it is remarkably poorly understood . This project will seek to determine how additional genetic changes in an established tumour alter the microenvironment and, conversely, how the tumour microenvironment influences the selective advantage or disadvantage of the cancer cells with additional mutations . The ultimate goal is to develop sufficient understanding to limit the ongoing evolution of heterogeneous tumours and thereby reduce the emergence of therapy resistant disease.
To pursue the goals of this project we will use an already established system for generating intra-tumour heterogeneity in tumours in mouse models of cancer. This system exploits Cre-lox recombination to drive the sub-clonal expression of oncogenes linked to the expression of fluorescent proteins that enable imaging of the tumour regions with additional genetic changes. A combined approach employing intravital imaging , multiplexed histology, RNA sequencing and pharmacological perturbations will be used to understand how changes in tumour genotype influence the tumour microenvironment and whether changes in tumour genotype and selectively favoured in the long term. This work will also be linked to computational modelling of competition between cancer sub-clone in different environments . Ultimately, strategies predicted to limit the emergence of resistant disease will be tested in pre-clinical models.
The candidate should be enthusiastic about understanding how tumours function as a system of communicating cell types. They should be comfortable interacting with researchers from different disciplines and highly motivated. A background in either cell signalling or tissue biology would be advantageous. Suitable degree subjects include, but are not limited to, biochemistry, bioengineering, cell biology, genetics, physiology, and zoology. Technical expertise in either molecular biology or imaging methods is desirable and a quantitative mind-set would be an asset for interactions with computational biologists building in silico models of cancer evolution. Good record keeping and time management will also be important.
Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2020 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) 13 NOVEMBER 2019. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
1. McGranahan, N. and Swanton, C. (2015)
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution.
Cancer Cell 27: 15-26. PubMed abstract
2. Hirata, E. and Sahai, E. (2017)
Tumor microenvironment and differential responses to therapy.
Cold Spring Harbor Perspectives in Medicine 7: a026781. PubMed abstract
3. Hirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., . . . Sahai, E. (2015)
Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling.
Cancer Cell 27: 574-588. PubMed abstract
4. Basanta, D. and Anderson, A. R. A. (2017)
Homeostasis back and forth: An ecoevolutionary perspective of cancer.
Cold Spring Harbor Perspectives in Medicine 7: a028332. PubMed abstract