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Title:
Dissecting the protumourigenic activities of senescent cells in the development and relapse of paediatric diffuse midline glioma
Supervisors:
Juan Pedro Martinez-Barbera and David Michod
Project Description:
Diffuse Midline Glioma (DMG), previously termed diffuse intrinsic pontine glioma (DIPG), is a devastating paediatric brain cancer typically diagnosed in children 5-7 years old. The prognosis is abysmal with a 95% mortality at 2 years following diagnosis. The only effective treatment is radiotherapy, however this is palliative and the vast majority of tumours relapse 3-6 months post-RT with fatal consequences1. We hypothesise that senescent cells present in the tumour and tumour microenvironment (TME), as the consequence of oncogene-induced senescence and/or radiation-induced senescence, fuel tumour growth and relapse.
Senescence is a response to cellular stressors such as oncogenic signalling, replicative exhaustion and genotoxic agents. Upon senescence induction, cells enter a stable cell cycle arrest, which is maintained by critical pathways regulating cell cycle progression. Senescent cells can elicit cell non-autonomous activities through the senescence-associated secretory phenotype (SASP), a complex secretory programme composed of a multitude of cytokines and chemokines, growth factors, and other active chemicals. Robust evidence has shown that senescent cells can be protumourigenic and that senescent cell ablation or modulation of the SASP, can reduce tumour burden, increase mouse survival, decrease tumour relapse and alleviate the negative effects of anticancer treatment2,3.
Our preliminary data show the presence of senescent cells in DMG murine models during tumour development and after RT, both in cells within the tumour and in the tumour microenvironment (TME). We have also detected expression of senescent markers in human samples of paediatric DMG. Of translational relevance, we have shown that RT induces senescence in human DMG cell lines, resulting in a marked sensitivity to Navitoclax, a Bcl-xL, Bcl2 and Bcl-W inhibitor, both in cell lines and in a PDX model of DMG.
Building on these findings, we will address the following research questions: (i) which cell types are senescent during DMG-H3K27 development and post-RT?; (ii) what molecular and cellular mechanisms underlie their tumour-promoting activity?; (iii) can senotherapies improve RT clinical outcomes?
To address these questions and provide preclinical data to support senotherapy-based clinical trials in patients, the PhD student will:
(Aim 1) Reveal the cell types that become senescence, both within the tumour lineage and TME in developing and post-RT relapsed tumours. These cell populations will be molecularly characterised (e.g. scRNA-seq) in mouse tumours.
(Aim 2) Uncover the molecular and cellular mechanisms underlying the tumour-promoting activities of senescent cells using our DMG mouse models and the p16-FDR mouse line, which allow senescent detection, isolation and ablation4.
(Aim 3) Evaluate preclinically the efficacy of combination therapies of radiotherapy and senolytic treatments. Optimisation of these combination therapies will involve mathematical modelling, which will be carried out in collaboration with Dr Jamie Dean (UCL Faculty of Engineering Sciences).
This PhD student will acquire a deep understanding of the biology of DMG and senescence, enabling them to contribute to important research in these fields. Additionally, this project will facilitate the student to acquire cutting-edge technical skills, helping them to propel their research career.
References:
1. Hargrave D. Pediatric diffuse intrinsic pontine glioma: can optimism replace pessimism? CNS Oncol. 2012; 1(2):137-148.
2. Gonzalez-Meljem JM, Apps JR, Fraser HC, Martinez-Barbera JP. Paracrine roles of cellular senescence in promoting tumourigenesis. Br J Cancer. 2018; 118(10):1283-1288.
3. McHugh D, Sun B, Gutierrez-Muñoz C, et al. COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells. Nat Cell B
Contact Information:
JP Martinez-Barbera