Background: Cancers of the skin are the most common of all cancers and affect almost equally women and men. The number of cases is increasing rapidly, including for melanoma, one of the deadliest forms. Other skin cancer types such as basal cell carcinoma and cutaneous squamous cell carcinoma are thankfully less deadly but much more common. They too require fast intervention and are notoriously very hard to diagnose, especially at an early stage, without the help of a biopsy. Skin cancer diagnosis is most commonly derived from visual or digital inspection of a skin lesion by a trained professional, ideally including dermoscopy. Identification of suspicious skin lesions in primary care are typically followed by an urgent referral, leading to a skin biopsy and histopathological examination, in suspicious cases. Whilst primary care clinicians are generally accurate at recognising suspicious skin lesions (with melanoma having one of the lowest median primary care intervals), only around 15% of urgent referrals result in a malignancy diagnosis. Despite recent studies reporting on the promise of using artificial intelligence and machine learning algorithms for moderate improvement in sensitivity, this low positive predictive value results in a large number of skin biopsies performed unnecessarily every year in the UK which is distressing to the patient (long time-to-result and morbidities) and costly to the NHS which spends >£35M every year on unnecessary diagnostic procedures for skin cancer only.  

Aims: Our solution is to develop minimally invasive technologies to be used alongside visual inspection in primary care settings to provide an accurate diagnosis based on molecular biomarker signatures sampled near the suspicious lesion where their concentration is the highest. 

Methods: This project will develop and exploit novel microneedle skin patches to interrogate skin fluid in a rapid and painless manner. Tested on mouse models and also on human skin biopsies sourced from dermatologists and clinical oncologists, our patches will allow us to identify and clinically validate skin cancer-specific signatures within skin fluid. More specifically, we will explore pH in interstitial skin fluid as a “universal” skin cancer biomarker. 

Cancer cells are known to exhibit higher metabolic activity than normal cells, primarily due to their more active electron transport chain (ETC), located in the inner membrane of their mitochondria. This increased ETC activity generates a stronger proton gradient, which is counteracted by ion leakage through the inner membrane. In this project, we will explore the hypothesis that cancer cells possess a more active ETC without the corresponding ion leakage and produce less reactive oxygen species (ROS), thereby enhancing ATP production necessary for greater cell proliferation. We will focus on understanding the factors influencing ETC activity and leakage of ion channels. We will analyze

(i) ETC activity in cancer cells, via respiratory complex I, using and developing innovative electron paramagnetic resonance spectroscopy techniques,

(ii) metabolic efficiency via the ion leak channel located within the C subunit of the F1Fo ATP synthase,

(iii) ROS production in cancer cells.

By elucidating the relationship between ETC activity, oxidative phosphorylation efficiency, ATP synthesis, ROS production and cancer cell proliferation, we aim to develop novel strategies for cancer treatment and prevention. 

Stromal-dense tumours, characterised by stiff tumour microenvironments, exhibit treatment resistance and aggressive behaviour in cancers such as pancreatic and breast. While considerable research focuses on relieving intratumoural pressure for the purpose of improved drug delivery, little attention has been given to the role of mechanical stress on cellular responses to radiation. Emerging evidence suggests mechanical stress, such as extracellular matrix-induced compressive stress, influences cancer cells' radiosensitivity through mechanoreceptors and mechanotransducers. Further, several groups have presented in vitro evidence supporting enhancement of cancer cell radiosensitivity after shear stress applied using ultrasound stimulated microbubbles.  This project proposes to use novel technologies to monitor, for the first time,  the effects of mechanical stress, combined with radiation therapy, on cell membranes. As part of a multidisciplinary team that comprises experts in chemistry, biology, physics and oncology from Imperial and the Institute of Cancer Research the student will use an exciting new technology,  molecular rotors combined with fluorescence lifetime imaging microscopy (FLIM) that can be used to measure the viscosity of the cell membrane and other cellular components https://doi.org/10.1002/anie.202311233. Using this technology the student will explore the relationship between compressive TME and transient shear forces and cellular responses to radiation, hypothesising that mechanical stress is a key modulator of radiation-induced cancer cell death. This research aims to provide novel insights into optimising treatment strategies for mechanically stressed tumours.

(N.B Abstract was amended on 11th December)