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Kennedy Trust Prize Studentships

  • Project No: KIRC6
  • Intake: 2022 KIR Clinical

Supervisor:  Prof Kim Midwood 

Co-Supervisors:  Prof Stuart Winter, Dr Thomas Layton

PROJECT OVERVIEW

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease that is increasingly common, and which exhibits high mortality, or life changing morbidity for people who do survive.  HNSCC is a general term for tumours arising within the upper aerodigestive tract which includes the oral cavity, pharynx and larynx, and which is defined by significant inter-tumoural heterogeneity, and unpredictable treatment responses and outcomes.  Dysregulated crosstalk between the cellular and microbial components that comprise complex mucosal ecosystems has been implicated in HNSCC progression and outcomes (1). However, whilst detailed genomic analysis has predominantly focused on tumour cells (2), non-malignant cellular lineages, including stromal and immune cells, the tumour extracellular matrix, and the oral microbiome, remain understudied in HNSCC.  Moreover, systematic analysis of each of these components across distinct anatomical disease subsites is lacking.   This project focuses on dissecting tumour heterogeneity in primary tumour samples collected from the world leading Bleinheim Head and Neck Unit at the Churchill Hospital. Firstly, we aim to develop a translational pipeline enabling the collection, processing and analysis of freshly obtained head and neck cancer tissue, patient matched control tissue and blood samples, and oral rinse samples. Our groups expertise in sample preparation for transcriptomic sequencing (PMID:32488016; 31840071) will be applied to HNSCC to support the assimilation of clinical, cellular and transcriptomic data from tumours across stages, anatomical sub-sites (oral cavity, pharynx and larynx) and aetiologies. This resource will then be interrogated to explore the hypothesis that site-specific alterations in stromal cell-matrix networks define anatomically diverse modes of tumour development in HNSCC. 

There is increasing data to highlight the translational potential of HNSCC stroma research. Indeed, single cell transcriptomic analysis of oral cavity SCC revealed a prominent stromal compartment, with a high proportion of fibroblasts and immune cells, that, in contrast to high malignant cell heterogeneity, showed remarkable consistency across tumours from this sub-site (3). Despite this work, there are currently no cellular data that allow comparison with other disease sub-sites, nor with healthy tissue. In addition, although dysregulated extracellular matrix composition is linked to tumour behaviour and outcomes in HNSCC (4) the extent of its diversity across anatomical subsites in the upper aerodigestive tract is not known, with quantitative proteomic analysis limited to in vitro models (5) to date.  Leveraging the power of integrated scRNA seq, proteomic and in vivo imaging assays, comparative analysis of the cellular and matrix components of healthy and tumour tissue from oral cavity, laryngeal, and pharyngeal sites will enable us to map the pathological ecosystem during carcinogenesis of the upper aerodigestive tract. These data will provide crucial insights into localized HNSCC pathogenesis, and guide advancement of stromal-targeted therapies by revealing distinct and shared pathways across different anatomical subsites. In parallel, building this repository of annotated and phenotyped clinical material will provide the foundation for further detailed analysis of other compartments of HNSCC that currently remain unexplored.

KEYWORDS

Tumour microenvironment, stroma, extracellular matrix, immune-oncology, microbiome.

TRAINING OPPORTUNITIES

The successful candidate will benefit from supervision by a surgeon scientist with a focus on head and neck cancer, a renowned authority on matrix biology, as well as a junior clinician scientist with expertise in computational biology and translational research.The candidate will be based in the modern building and laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the field of immunology, with a strong emphasis on clinical translation. The project will leverage the use of well characterized human samples, relevant functional assays in addition to cutting edge bioinformatics pipelines. In summary, you will be working within:

  • Cutting-edge cancer biology and next generation sequencing techniques available in-house, including tissue culture, flow cytometry, imaging assays, and single cell RNA-seq.
  • Well-established DPhil programme with defined milestones, ample training opportunities within the University and Department, and access to university/department-wide seminars by world-leading scientists.
  • Emphasis on translational work: findings from freshly obtained human samples can have a high impact on future therapeutic development 
  • Highly collaborative environment with expertise ranging from molecular and cell biology to in vivo imaging assays and computational biology / genomics analysis. You will also have the opportunity to participate in several other collaborations within the University of Oxford. 

KEY PUBLICATIONS

  1. Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020 Nov 26;6(1):1–22. 
  2. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer. 2018 May;18(5):269–82.
  3. Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017 Dec 14;171(7):1611-1624.e24. 
  4. Saint A, Van Obberghen-Schilling E. The role of the tumor matrix environment in progression of head and neck cancer. Current Opinion in Oncology. 2021 May;33(3):168–74. 
  5. Gopal, S., Veracini, L., Grall, D. et al. Fibronectin-guided migration of carcinoma collectives. Nat Commun 8, 14105 (2017). https://doi.org/10.1038/ncomms14105

THEMES

Oncology, Tissue Biology, Inflammation, Translational Medicine

CONTACT

Prof. Kim Midwood

Email: kim.midwood@kennedy.ox.ac.uk