About the Project
Background and significance:
Oral squamous cell carcinoma (OSCC) is one of the top ten cancers worldwide, with over 300,000 cases annually, and incidence is increasing both worldwide and in the UK (in the UK, incidence has increased by 23% over the past decade). The majority of cases are HPV-negative. HPV-negative OSCC is a deadly disease with frequent metastatic spread, which is the single most important predictor of outcome (1). It is also exceptionally amenable to in vitro experimental modelling of human tumour behaviour. This is due to the excellent recapitulation of in vivo tumour heterogeneity by established OSCC cell lines (2, 3).
Tumours are infiltrated by an array of different cell types that interact with the tumour and greatly influence tumour behaviour and disease course (4). In HPV-negative OSCC, an important category of tumour infiltrating cells is the immune cell infiltrate, which contains an abundance of macrophages and T-cells (5). The makeup of the immune cell infiltrate has a marked impact on clinical outcome (6). Tumour infiltrating T-cells are a particular indicator of favourable prognosis in OSCC (7), whereas tumour associated macrophages (TAMs) are an indicator of poor prognosis (8). TAMs act to suppress T-cells, and therefore the makeup of the immune cell infiltrate has a major bearing on the response to immunotherapy techniques that seek to enhance the T-cell response to the tumour (9, 10). The makeup of the immune cell infiltrate is controlled by factors released by the tumour, and in this way each tumour determines its own immune cell infiltrate (9, 11). This raises the prospect that genetic and cellular profiling of the tumour may enable prediction of the immune cell infiltrate and thus selection of the best immunotherapeutic approach for the patient.
Cancer stem cells (CSCs), the sub-population of tumour cells that possess tumour-initiating potential (12, 13), adopt phenotypes that drive tumour invasion and metastasis (14, 15) and express heightened resistance to therapy (2, 16). These cells are therefore of particular importance to tumour progression, and present a promising target for development of drugs that can stop metastasis. We have recently modelled the central role of CSCs in progression of OSCC (3, 14). In animal models of SCC, it has now been shown that CSCs interact with the immune infiltrate in order to create a permissive microenvironment that sustains their CSC phenotype and promotes tumour progression (17). This work now needs to be brought into a clinically relevant human OSCC model; understanding these interactions in human tumours may enable development of immunotherapeutic approaches that halt tumour progression by targeting the interactions between immune cells and CSCs.
Hypothesis and aims:
We hypothesise that the mutational profile of the tumour generates heterogeneity between patients in tumour-immune interactions, which are mediated by CSCs. This plays an important role in determining the cellular profile of the immune infiltrate in OSCC, which influences tumour progression.
We propose to test this hypothesis through the following aims:
(a) Characterise the genetic drivers and the immune infiltrate in a retrospective cohort of FFPE OSCC specimens stratified by pathological prognosis, identifying associations between genetic drivers, immune components, and prognosis.
(b) Test heterocellular interactions between defined tumour and immune cell populations in a tumour-on-a-chip device.
(c) Assess the role of CSCs in mediating these interactions, and identify the key signalling molecules. Determine how these signalling molecules contribute mechanistically to the maintenance of CSCs and formation of the immune cell infiltrate.
Environment and supervision:
This project will benefit from the state of the art facilities of the Blizard Institute, which have been created and funded to support cutting-edge multi-disciplinary research (www.qmul.ac.uk/blizard/research/core-facilities/). We have assembled an experienced multi-disciplinary team to manage this project. The project will be led by two OSCC experts (Dr Adrian Biddle, Blizard Institute; Dr Muy-Teck Teh, Institute of Dentistry) (2, 3, 14, 19, 20) and a head and neck pathologist (Dr Hannah Cottom, Barts Health) (3, 21, 22).
How to apply
To apply, please click the 'institution website' button.
The successful candidate must be a registered dental clinician in the UK.
References
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2. Biddle A, Gammon L, Liang X, Costea DE, Mackenzie IC. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine. 2016;4:138-45.
3. Youssef G, Gammon L, Ambler L, Wicker B, Patel S, Cottom H, et al., Biddle A. Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis. bioRxiv. 2020:2020.04.07.029009.
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17. Taniguchi S, Elhance A, Van Duzer A, Kumar S, Leitenberger JJ, Oshimori N. Tumor-initiating cells establish an IL-33-TGF-beta niche signaling loop to promote cancer progression. Science. 2020;369(6501).
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20. Teh MT, Hutchison IL, Costea DE, Neppelberg E, Liavaag PG, Purdie K, et al. Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. Int J Cancer. 2013;132(9):2095-106.
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22. Barry P, Vatsiou A, Spiteri I, Nichol D, Cresswell GD, Acar A, Cottom H, et al. The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer. Clin Cancer Res. 2018;24(19):4763-70.
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