Cancer Neuroscience: Investigating the impact of non-CNS tumours on neuronal plasticity in the brain

About the Project

To apply, please contact Dr Graham Sheridan at Graham.Sheridan@nottingham.ac.uk.

Cancer is one of the leading causes of death worldwide, resulting in approximately 18 million new cases and 10 million deaths each year. One of the most common complaints amongst cancer patients, including patients in remission, are subtle but significant neurocognitive changes, such as memory impairment.

It is estimated that 75% of cancer patients experience cognitive problems throughout their disease progression and its treatment phases. Interestingly, cognitive disturbances are not only endured by people with central nervous system (CNS) tumours, but are also common in patients that possess tumours growing outside of the CNS, i.e. cancers that have not yet metastasized to the brain, such as primary breast cancer.

Cancer patients can develop cognitive deficits as a result of the neurotoxic side-effects of antineoplastic drug treatment regimens, leading to a condition known as ‘chemo-brain’ or ‘chemo-fog’. Therefore, many studies have suggested that chemotherapy is the primary cause of the cognitive dysfunctions often reported by cancer patients with non-CNS tumours. The most common cognitive complaints reported by patients that have received chemotherapy include deficits in memory retention, executive functioning, psychomotor speed, verbal memory, and attention.

However, up to 35% of cancer patients with non-CNS tumours experience cognitive deficits prior to receiving any therapeutic interventions, such as surgery, radiotherapy, chemotherapy and hormonal therapy. The mechanisms underlying pre-chemotherapy cognitive decline or “cancer-related cognitive impairment” are less well known and will be the focus of this PhD project.

The successful PhD candidate will investigate the cellular and molecular dysregulations induced in the brain in response to non-CNS tumour growth (e.g. breast cancer). This is a multidisciplinary project in the relatively novel research field of Cancer Neuroscience. The PhD student will gain expertise not only in the fields of neuroscience and pharmacology, but also cancer biology, immunology and regenerative medicine. The overall goal of the project is to investigate the impact of non-CNS tumours on neuronal plasticity and glial cell homeostasis in key brain areas involved in learning, memory and executive functions.

The project will involve generating and analysing proteomic datasets from different brain regions to pinpoint key drug targets and cellular signalling pathways that may lead to cancer-related cognitive impairment (CRCI). The PhD candidate will also develop novel 3-dimensional cell culture models of the brain that can be co-cultured with tumour spheroids so as to mimic the in vivo microenvironment of brain tissue that is exposed to biochemical factors released by non-CNS tumours.

As such, the PhD candidate will be trained in the culture of organotypic brain slices, cerebral organoids, and 3D tumour/immune cell spheroid models of disease. These novel ex vivo co-culture models will enable the student to interrogate how non-CNS tumours impact the structure of the brain (e.g. myelin and blood vessels), the neuroinflammatory state of the brain (e.g. microglia and astrocyte reactivity), molecular mechanisms of cognitive decline (using techniques such as immunofluorescence, confocal microscopy, ELISA, Western blot, mass spectrometry and PCR), and changes in synaptic plasticity in the hippocampus (e.g. using live-cell calcium imaging or electrophysiology techniques).

Funding Notes

3 – 4 years full time

Self-funded PhD students only

References

1. Mampay M, Flint MS, SHERIDAN GK (2021) Tumour brain: Pretreatment cognitive and affective disorders caused by peripheral cancers. British Journal of Pharmacology 178: 3977-3996
2. SHERIDAN GK, Murphy KJ (2013) Neuron–glia crosstalk in health and disease: fractalkine and CX3CR1 take centre stage. Open biology 3: 130181