About the Project
Please note this PhD is for clinicians only
The most common subtype of lung cancer in the UK is lung squamous cell carcinoma (LUSC), constituting 43% of lung cancers in England and Wales. LUSC, similar to other lung cancer subtypes, develops through a preinvasive phase, transitioning from normal epithelium to mild, moderate (low-grade lesions; LGLs) and severe dysplasia and then to carcinoma-in-situ (CIS) (high-grade lesions; HGLs), before progressing to invasive cancer.
The aim of this project is to decipher the key processes leading normal airway epithelium to evolve into pre-cancerous and then invasive cancer. Defining these processes and understanding how squamous cancer evades immune surveillance will improve both our understanding of the key pathogenetic steps to cancer and enable us to design novel therapeutics to prevent pre-cancerous epithelium progressing to fully invasive cancer.
This project will use tissue from two on-going CRUK-funded clinical trials based at UCL Hospitals Trust and Barts Health NHS Trust: EARL and ASCENT. EARL is a longitudinal follow-up study of precancerous lesions after randomisation to electrocautery or not. In ASCENT, early screen-detected cancers (detected in the SUMMIT study, CT screening of 25,000 people in NC, NE and SE London) and related normal and pre-cancerous tissues are collected post resection.
Work from the Janes laboratory has shown that CIS lesions that progress to invasive cancer have distinct genomic, epigenomic and transcriptomic profiles that distinguish them from lesions that regress. At a molecular level, progressive lesions look more like cancer while regressive lesions maintain a transcriptomic and epigenetic profile close to normal epithelial cells. From these data we can generate hypotheses about the key molecular events that predict progression to cancer but little about the chronology, nor the targetable pathogenic steps dictating progression or regression. Moreover, whilst invasive cancers are known to be heterogenous3, the clonal structure of preinvasive lesions remains unclear. This has therapeutic implications as monotherapy may be ineffective against a highly heterogenous lesion.
We therefore wish to use these unique tissues and clinical data to define the clonal structure and signalling networks dictating progression of preinvasive lesions through high-resolution molecular profiling.
The aims of the project are:
• Use the longitudinally collected pre-cancerous tissues from EARL to estimate clonal structure using bulk sequencing data from preinvasive lesions
• Use single cell somatic copy number aberrations and transcriptomic signatures in CIS lesions, and importantly in matched CIS and contiguous LUSC from the ASCENT trial, to define clonality at a single-cell level and characterise phenotypic variations between distinct subclones and their interactions with the tumour microenvironment
• Use ASCENT resection samples in collaboration with the Sanger Institute to carry out targeted in situ mutational sequencing of the precancerous lesions and the adjacent cancer. This technique will outline the clonal dynamics of the precancer and related cancer in a spatial context, identifying the presence and molecular footprint of any dominant clone and its relationship with immune cells, improving our ability to develop targets for a cancer interception strategy
This clinical fellowship would be suitable for a wide range of candidate specialties due to the basic training available in lab techniques and bioinformatics, particularly oncology, respiratory and ENT/Head and Neck.
Potential placement opportunities
The fellow would have the opportunity to spend time in Boston in the single cell analysis informatic group headed by Avrum Spira as part of the Stand Up 2 Cancer-funded collaboration with Boston University.
For further details on how to apply please visit the CRUK CoL Clinical Research Training Fellowship programme web page: https://www.colcc.ac.uk/clinical-research-training-fellowships-crtf/
Funding Notes
The funding for this fellowship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website https://www.ukcisa.org.uk/Information--Advice/Fees-and-Money/England-fee-status#layer-6082. Please note that we will only be able to offer fellowships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).
References
Teixeira, V.H. et al. Deciphering the genomic, epigenomic and transcriptomic landscapes of pre invasive lung cancer lesions. Nat Med. 2019 Mar;25(3):517-525. doi: 10.1038/s41591-018-0323-0. (2019)
Pennycuick, A. et al. Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer Cancer Discovery doi: 10.1158/2159-8290.CD-19-1366. (2020)
Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium.
Nature. 2020 Feb;578(7794):266-272. doi: 10.1038/s41586-020-1961-1. (2020)
Efremova , M. et al. CellPhoneDB: Inferring cell-cell communication from combined expression of multi-subunit receptor-ligand complexes. Nature Protocols (2020) 15(4):1484-1506. doi: 10.1038/s41596-020-0292-x.(2020)
Efremova, M. and Teichmann, S. A. Computational methods for single-cell omics across modalities. Nature Methods, 17(1):14-17. doi: 10.1038/s41592-019-0692-4 (2020)
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