Molecular and Cellular Mechanisms Underlying Pituitary Tumours

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

To win the war against cancer, we need to understand not only the events that take place along the way during its development, but also its origins. Advanced cancer usually contains cells that are highly abnormal compared with normal cells in the tissue where the cancer is developing. These cancer cells have the capacity to adapt to different environments and to change their genetic material, which contributes to the development of resistance to anti-cancer treatments. At the initial stages of cancer formation, however, cancer cells are physiologically more normal, carry fewer genetic changes and are easier to target and eliminate. Research aiming to develop new tools for early cancer detection as well as to target cancer cells at the initial stages of tumour formation are needed to boost survival rates and to minimise the damaging effects of both advanced cancer and the intensive treatments required to eradicate it.

To achieve this goal, we need to investigate the initial stages of cancer development, which are difficult to detect in humans, as they mostly go unnoticed. However, animal models, and in particular mice have proven to be excellent tools to understand the origins of cancer. Research from several groups has established a concept, referred to as the 'cancer stem cell paradigm', whereby tissue-specific stem cells are the origins of several tumours and cancers in mice and humans. This model proposes that when normal stem cells become mutated (i.e. the DNA changes in comparison with a normal stem cell), they give rise to cancer stem cells, which can proliferate and give rise to daughter cells that form the tumour. Essentially, cancer stem cells are the cell-of-origin of the tumours, with important implications for cancer treatment. For example, cancer stem cells are often resistant to therapies and although present in very low numbers, they can cause regrowth of the tumour if they are not destroyed. Cancer therapies should therefore aim to target the tumour mass as well as the cancer stem cells.

We have recently generated mouse models for a type of human tumour called adamantinomatous craniopharyngioma (ACP). This is an aggressive tumour that develops in the pituitary gland, an essential organ located under the brain that controls critical physiological functions such as growth, reproduction and metabolism. ACP is the most common pituitary tumour in children and young adults and the third most common brain tumour in children. ACP is associated with a poor quality of life of the patients due to compression or infiltration of the brain and can be fatal. Current treatments are surgery and/or radiotherapy, but these are not ideal and cause long-term side effects in the patients. Typical symptoms of ACP patients include obesity, diabetes mellitus type 2 and total failure of pituitary gland function.

Our research has revealed that pituitary stem cells are central players in the generation of ACP. However, contrary to the cancer stem cell paradigm, when these stem cells are mutated they do not divide and give rise to the tumour, instead they send signals to the surrounding cells, which eventually start proliferating uncontrollably to produce a pituitary tumour. Therefore, mutated stem cells instruct nearby cells to generate a tumour, a novel model that is conceptually different to the cancer stem cell paradigm. In this proposal we aim to investigate the mechanisms underlying this novel role for stem cells in cancer. Our goal is to improve our knowledge on the initial steps of tumour formation using our mouse models. This will lead to better management of ACP patients, and will also have implications in other tumours and cancers in which stem cells may have tumour-inducing capacity.

Technical Summary

We have generated and published mouse models of human adamantinomatous craniopharyngioma (ACP) and validated that these are relevant to understand the aetiology and pathogenesis of the human tumours. Using these mice, we have recently uncovered a paracrine model of tumorigenesis, whereby mutated Sox2+ pituitary stem cells secrete signalling factors that act on surrounding cells resulting in cell transformation and tumorigenesis in a non-cell autonomous manner. Our data suggest that cell senescence and low-grade senescence-induced inflammation are critical players in tumour initiation in both mouse and human ACP. Many questions remain unanswered about this novel mechanism of oncogenesis:
(i) Which molecular pathways promote the abnormal expression of secreted factors by mutated Sox2+ stem cells?
(ii) Which are the critical secreted signals that induce the tumours?
(iii) Could inhibition of these signals result in the development of novel chemical treatments for the patients?
(iv) Which is the cell-of-origin of the tumours?
Answering these questions will provide mechanistic insights into the paracrine model of tumorigenesis to further understand the pathophysiology of pituitary tumours, and with broader implications for oncology and the role of somatic stem cells, senescence and inflammation in cancer (Aim 1). In addition, it will lead to a better understanding of the initial steps of tumour formation and the identification of the cell-of-origin of ACP (Aim 2), which will facilitate the development of new tools for early diagnosis and will allow validation of targeted treatments against oncogenic signalling pathways. To achieve this, I will use a multidisciplinary approach combining:
(i) Mouse genetics (genetic tracing, gene deletion, preclinical studies using small-molecule inhibitors).
(ii) Cell isolation by flow cytometry.
(iii) Molecular biology (gene expression and mutational profiling by RNA-Seq).
(iv) Developmental biology (generation of chimeras).

Planned Impact

1. The long-term beneficiaries of this research include patients suffering from pituitary tumours and their families as well as health-care providers and social workers. Results of the proposed research will reveal genes and pathways that are dysregulated in adamantinomatous craniopharyngioma (ACP), which could lead to the discovery of new biomarkers of disease and specific targeted treatments. For example, around half of ACP tumours are very infiltrative into the brain and prone to recurrence, whilst others are more localised and recur less frequently, but there are no biomarkers available at present that can predict tumour behaviour. Because of the strong links to Great Ormond Street Hospital for Children (GOSH), and the established collaborations with clinicians (e.g. Thomas Jacques, neuropathologist), we will assess the potential value as a predictable biomarker of the dysregulated genes that will be identified in the proposed research.

Another unmet clinical need for these childhood tumours is that there are currently no specific treatments. Surgery and/or radiotherapy are not ideal and associated with high morbidity in the patients. Our research will highlight pathways with oncogenic potential that are dysregulated in the human tumours, which could be targeted with specific inhibitors in future research projects. We recently started a pre-clinical trial using our mouse models to assess the efficacy of hedgehog inhibitors (funded by Great Ormond Street Hospital for Children Charity (GOSHCC)). These studies are being performed in close collaboration with Dr Darren Hargrave, an oncologist at GOSH, who specialises in brain tumours and the UK coordinator for several ongoing human clinical trials worldwide. Dr Hargrave is ideally placed to translate our results into the clinical setting. Moreover, his contacts with pharmacological industries will facilitate the use of inhibitors that are currently being tested for other tumours and cancers, which will expedite the use of these drugs in children with ACP.

2. Organisations such as charities working with patients and their families, providing lay summaries and information on medical conditions, may find the results from this study of use for inclusion in their communications, which will in turn help improve social welfare and well-being. These activities usually contribute towards increasing public awareness of science and the use of mice for biomedical research, as the benefit to child health is specially highlighted and of relevance to patients and their parents/relatives/friends.

3. Finally, pharmaceutical companies could be interested in the proposed research. Usually, this industry has not been interested in specific development of drugs for childhood tumours. The reason is that only one to two per cent of all tumours and cancers affect children, and therefore the 'market' is not big enough to recover the costs of drug development and production. Because this is not ethically acceptable, there have been governmental incentives to the industry to include childhood tumours in ongoing clinical trials for adult cancers, promoting in this way the development of specific protocols and applications of the drugs specifically for children. We will use the results from the proposed research to engage with pharmaceutical industries aiming to extend the use of drugs to children with ACP. For example, through Dr Hargrave we have initiated contact with Novartis, as they are currently testing the efficacy of the hedgehog pathway inhibitor LDE-225 for the treatment of medulloblastoma (the most common brain tumour in children). Our aim is to prove the principle that LDE-225 could potentially be used for treatment of human ACP (GOSHCC grant). A similar approach will be used with those inhibitors that are shown to have a beneficial effect in the proposed preclinical studies.

Publications

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Buhl JL (2019) The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma. in Clinical cancer research : an official journal of the American Association for Cancer Research

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Carreno G (2017) Stem cells and their role in pituitary tumorigenesis. in Molecular and cellular endocrinology

 
Description CRUK Science Committee Research Awards
Amount £1,537,452 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2019 
End 01/2024
 
Description Cancer Research UK. Clinical PhD studentship Research Fellowship
Amount £250,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 08/2017
 
Description Children with Cancer UK; Collaborative grants
Amount £458,728 (GBP)
Organisation Children with Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2018
 
Description Children's Cancer and Leukemia Group project
Amount £9,975 (GBP)
Organisation Children's Cancer and Leukaemia Group (CCLG) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 07/2015
 
Description EVEREST- Paediatric research and Innovation centre for low grade brain tumours
Amount £5,000,000 (GBP)
Funding ID GN-000382 
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2017 
End 05/2022
 
Description Molecular characterisation of human childhood craniopharyngioma
Amount £27,000 (GBP)
Organisation Great Ormond Street Hospital (GOSH) 
Department NIHR Great Ormond Street Biomedical Research Centre
Sector Public
Country United Kingdom
Start 11/2014 
 
Description Molecular profiling of relapsing craniopharyngioma
Amount £10,000 (GBP)
Funding ID CCLGA 2017 05 
Organisation Children's Cancer and Leukaemia Group (CCLG) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 09/2018
 
Description Pre-clinicl tiral of anti-inflammatory antibodies in a mouse model of adamantinomatous craniopharyngioma
Amount $75,000 (USD)
Organisation The Morgan Adams Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2017 
End 05/2019
 
Description Project grant application to the MRC
Amount £965,381 (GBP)
Funding ID 164126 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2015 
End 12/2017
 
Description SIGNAL - Striking Insensitive Paediatric Gliomas Through Network Analysis
Amount £400,000 (GBP)
Funding ID GN-000359 
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2018
 
Description The Brain Tumour Charity: Quests for Cures
Amount £1,058,220 (GBP)
Organisation The Brain Tumour Charity 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 08/2023
 
Description Undersatanding the role of senescence and NFkB signalling in pituitary tumours
Amount £73,967 (GBP)
Funding ID STU5 
Organisation The Child Health Research Charitable Incorporated Organisation 
Sector Academic/University
Country United Kingdom
Start 10/2016 
End 09/2019
 
Title RNA-seq and whole exome sequencing datsets 
Description We have performed several experiments aiming to profile specific tumour cells within human craniopharyngioma as well as the mouse models of these tumours. Whole-exome sequencing of mouse tumours have also been carried out. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact No impact yet 
 
Description Molecular characterisation of human adamantinomatous craniopharyngioma 
Organisation Children's Cancer and Leukaemia Group (CCLG)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are characterising these paediatric tumours and reporting our results
Collaborator Contribution The CCLG will provide tumour samples, matching blood DNA, and other human tissues that are required for our projects
Impact Still too early
Start Year 2014
 
Description Molecular characterisation of human childhood craniopharyngioma 
Organisation Great Ormond Street Hospital (GOSH)
Department Centre for Translational Genomics (GOSgene)
Country United Kingdom 
Sector Hospitals 
PI Contribution GOSgene sponsored a study to perform whole genome sequencing and gene expression profiling of 5 human craniopharyngioma samples. Later, I applied to CCLG (Children's Cancer and Leukaemia Group) for a pilot grant to complement the proposed studies and increase the number of samples analysed. This grant application was also successful. The sponsorship by GOSgene was instrumental in attracting co-funding. The studies have been initiated and I aim to get sufficient data to build a programme grant application by the end of 2015.
Collaborator Contribution GOSgene will perform the sequencing and subsequent bioinformatic analysis. A Clinical PhD Fellow in my lab will lead these studies and will work together with GOSgene research personnel. CCLG provided additional funds for reagents and sequencing.
Impact Too early; sequencing has been performed and is currently being analysed.
Start Year 2014
 
Description Preclinical evaluation of novel therapies against paediatric craniopharyngioma 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with Dr Simon Robinson (Institute of Cancer Research, Sutton) to evaluate novel therapies that have been identified through the project funding by the MRC. We will provide the mice and the drugs.
Collaborator Contribution Dr Robinson's group, in particular Dr Jessica Boult, will analyse the tumour growth by MRI.
Impact We have published a paper already (Boult et al 2017) and have another paper under review.
Start Year 2017
 
Description Preclinical studies in mouse models for human adamantinomatous craniopharyngioma (ACP) 
Organisation Institute of Cancer Research UK
Country United Kingdom 
Sector Academic/University 
PI Contribution We are transferring our mouse models and Dr. Chesler's Team is using them for testing specific small molecule inhibitors of pathogenic pathways. We have generated these unique mouse models.
Collaborator Contribution Dr. Chesler runs a 'mouse hospital'. This facility contains state-of-the-art equipment for imaging (e.g. MRI), personnel and capacity to perform pre-clinical studies in mice. We cannot do these studies as well as they do.
Impact Unique MRI images have been obtained which inform us on how these tumours develop in the mouse models. The first pre-clinical trial using a SHH pathway inhibitor has been finalised and data is currently being analysed. Other pre-clinical trials are under way
Start Year 2014
 
Description 8 Poster presentations and 6 invited talks in national and international scientific meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Posters and talks about my group's research

Colleagues and other researchers asked questions and wrote mails
Year(s) Of Engagement Activity 2013,2014,2015
 
Description Conferences in Boston, Munich, France, Liverpool, Bad Zwischenahn (Germany) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talks in National and international conferences and workshops
Year(s) Of Engagement Activity 2016