Cancer-related Cognitive Impairment: Investigating neuroimmune mechanisms linking peripheral tumours to dysfunctional synaptic plasticity in the brain

About the project

About the Project To apply, please contact Dr Graham Sheridan at Graham.Sheridan@nottingham.ac.uk . Project overview Cancer is increasingly recognised as a systemic disease that produces pathophysiological effects in organs distant from the primary tumour site. Clinically, one of the most concerning remote effects of tumour growth is chronic cognitive impairment, manifesting as memory deficits, attentional problems and reduced executive functioning. While chemotherapy is a well-documented contributor to these deficits, studies show that a substantial proportion of patients (approx. 35%) with non-central tumours (e.g. primary breast cancer) experience cognitive decline even before any therapy is administered. These findings raise a fundamental mechanistic question: how do tumours outside the central nervous system (CNS) influence neural circuits and plasticity at a distance? This PhD project aims to identify tumour‑derived molecular signals that disrupt neuroimmune pathways, induce glial cell reactivity, disrupt synaptic plasticity, and ultimately impair the neural circuits that support learning and memory. Solving this problem has the potential to transform how cognitive decline in cancer patients is detected, prevented, and treated. Scientific aims and central questions This project aligns with the rapidly growing field of Cancer Neuroscience, exploring how tumours communicate with the nervous system. The PhD student will address several mechanistic questions: 1. Which tumour‑derived molecules (cytokines, extracellular vesicles, metabolites) reach the brain and how do astrocytes, microglia, and cells of the neurovascular unit respond to these signals? 2. Are the central effects of tumour growth region‑specific or a non-targeted response to immune suppression/ systemic inflammation? 3. How do hippocampal and prefrontal cortical networks respond to chronic tumour growth in terms of synaptic proteome alterations, calcium signalling, and electrophysiological properties of neurons? Addressing these questions will illuminate how tumour activity outside the CNS drives molecular and cellular changes in the brain before the commencement of anti-neoplastic therapies. Methodological Approach The successful candidate will work at the interface of molecular neuroscience, tumour biology, and neuroimmunology, using advanced experimental techniques to dissect tumour–brain communication. Techniques include: · Developing 3D co-culture platforms, including organotypic brain slices and cerebral organoids co-cultured with tumour and immune-cell spheroids, to observe in real-time how tumour-released factors alter calcium oscillations, glial cell dynamics, and neural network excitability. · Quantitative mass spectrometry across multiple brain regions to identify synaptic proteins and signalling pathways altered by tumour growth. · Integration of molecular biology, proteomics, Western blotting, ELISA, PCR, and pathway‑level bioinformatics to characterise key neuroinflammatory mediators, synaptic proteins, and plasticity‑related pathways underlying cancer-related cognitive impairment. Training, impact and career development This PhD offers the opportunity to make discoveries that could fundamentally change how we think about cancer and cognition. It is ideally suited to ambitious students who want to push scientific boundaries and contribute to a rapidly expanding interdisciplinary field. The student will join a collaborative, interdisciplinary team and receive rigorous training in molecular neuroimmunology, proteomics, advanced imaging and 3D culture technologies. Graduates will be well placed for careers in academic research, translational science, or industry roles that bridge neuroscience and oncology.

Research areas