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Title:
Understanding the function of senescent cells in genetic models of paediatric low-grade brain tumours.
Supervisors:
Juan Pedro Martinez-Barbera and Laura Donovan
Project Description:
Low-grade paediatric brain tumours have been understudied for decades, however it is now clear that despite their histological benign nature, these tumours can behave aggressively in the clinic. Paediatric onset craniopharyngioma (pCP) and paediatric low-grade gliomas (pLGG) are the most common brain tumours in children and young adults and can be associated with high morbidity and poor quality of life for the patients. There is a need to improve current treatments, and to achieve this goal, a better understanding of the tumour biology is needed1.
pCP and pLGG are characterised by the present of senescent cells. Senescence is a cellular state characterised by a stable cell cycle arrest and the concomitant activation of a secretory phenotype termed SASP (Senescence-Associated Secretory Phenotype). The SASP includes multiple growth factors, inflammatory mediators and extracellular matrix modifiers, which modify the tumour microenvironment promoting tumour initiation, growth, progression and metastasis. Because these crucial roles in cancer, it is becoming increasingly clear that efficient cancer therapies must target both the proliferative and the senescent compartments2.
The supervisor’s research has demonstrated that senescent cells are relevant in the context of pCP and pLGG. Senescent cells are able to induce tumour initiation in a murine model of ACP and similar senescent cells are present in human ACP in the invasive front, where they drive tumour invasion in the brain3. Likewise, our research has shown that senescent cells, induced by anti-cancer treatment in murine models of pLGG, can be removed using senolytics (drugs that kill senescent cells) to reduce tumour growth4. However, many questions remain: Which cell types enter senescence upon oncogenic stimulation or after cancer therapy?; What are the mechanisms promoting tumour development or relapse after therapy?; what is the potential therapeutic value of anti-senescence therapies?.
The main goal of this proposal is to study the role of senescent cells in pCP and pLGG using preclinical models, including cell lines, organoids, genetic mouse models and patient-derived xenografts, and validate the findings in human tumours.
Specific objectives:
1. Identify the cell types that become senescent both during tumour development and after anti-cancer therapy. This will be achieved combining single cell RNA sequencing approaches with immunohistochemistry. This will be achieved in year 1.
2. Ablate these senescent cells to reveal their functions in tumourigenesis. We have developed unique models that allow the ablation of senescent cells and we also have access to new senolytics. This objective will be achieved in year 2.
3. Characterise the senescent compartment in human tumour samples. These samples will be analysed by immunohistochemistry and, in collaboration with research partners in Heidelberg and Harvard, computationally to determine enrichment for senescent signatures. (years 2-3).
Overall, the PhD student will acquire a solid knowledge in the new and rapidly growing area of senescence in cancer, contributing to important research in this field. Additionally, this project will facilitate the use of cutting-edge technical approaches, providing essential skills for a career in research.
References:
1. Carreno G, Guiho R, Martinez-Barbera JP. Cell senescence in neuropathology: A focus on neurodegeneration and tumours. Neuropathol Appl Neurobiol. 2021; 47(3):359-378.
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. Gonzalez-Meljem JM, Haston S, Carreno G, et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat Commun. 2017; 8(1):1819.
4. Selt F, Sigaud R, Valinciute G, et al. BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astr
Contact Information:
JP Martinez-Barbera