Title: Characterisation of senescence-associated secretory phenotype in glioblastoma
Funder: The Academy of Medical Sciences

Abstract: Cellular senescence plays a pivotal role in cancer progression. The variable impact of senescence through its secretome, senescence-associated secretory phenotype (SASP) leads to paradoxical effects in tumourigenesis. Critically, the cell of origin and tumour tissue dictates the downstream impact of senescence to either promote or suppress tumourigenesis through T-cell and macrophage functions. In glioblastoma (GBM) the most aggressive primary malignant brain tumour, increased number of M2 tumour associated macrophage (TAM) infiltration correlates with a poorer prognosis. Current understanding of SASP and senescence in GBM in relation to TAMs is unexplored and requires investigating. Our aim is to characterise SASP and its involvement in mediating myeloid cell infiltration in GBM. To achieve our aim we will use human GBM tissue throughout. The first objective will be to identify senescent cells, focussing on spatial localisation and cellular morphology using immunohistochemistry and immunofluorescence. To determine SASP, we will analyse dissociated GBM tissue using multiplex cytokine assays and qPCR to characterise a pro or anti-inflammatory signature. Thereafter, flow cytometry and flow-cell sorting will immunophenotype and isolate senescent cells for downstream secretome analysis respectively. The final objective will use the Hyperion, an in-depth imaging mass cytometry tool with high-dimensional analysis, to configure the tumour microenvironment (TME) in GBM and begin to construct neighbourhoods of inflammatory cells and their relationship with senescence. The overarching aim is discover mechanistic pathways of senescence that mediate trafficking of anti-inflammatory TAMs to the TME in order to re-educate macrophages towards an anti-tumourigenic phenotype in GBM patients.

Lay abstract: Glioblastoma (GBM) is a devastating disease and an incurable brain cancer. Despite best treatments, only 3% of patients survive up-to 5-years. Our current understanding shows that our body’s defence system made up of immune cells fails to overcome cancer growth. Unexpectedly, one particular group of immune cells called macrophages, populate the GBM cancer to support its progression. In other cancers, there is a process where cells in the body stop dividing, this is called senescence. Senescent cells can either help or attack cancer. An example is breast cancer, senescence releases a large group of signals called senescence-associated secretory phenotype (SASP) and works with macrophages to allow cancer growth. We do not know if senescence exists in GBM. The aim of this research is to study senescence in GBM and to explore the role of SASP in cancer and how it interacts with macrophages. For this study, we will use patient GBM samples to locate the senescent cells in the cancer, check if they are releasing SASP and explore their communication with immune cells. Patients continue to suffer an inevitable fate with GBM and this work is a critical stepping-stone to understanding how immune cells and tumours cells interact and if they help the cancer. In the future, we aim to stop the macrophages from being manipulated and exploit them to target GBM cancer cells.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS