Fondation pour la Recherche Nuovo Soldati
Grants in cancer research

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Laureates 2011 - 2012

Isabelle Tromme
Nicolò Riggi
Guillaume Bergthold
Marc Pusztaszeri
Matthias Dettmer

Isabelle Tromme

Title of the project:Assessment of two methods to detect melanoma: dermoscopy and digital dermoscopy.

Place of the training course:Dermatology and epidemiology departments,
Catholic University of Louvain,
Brussels, Belgium.

Summary of the project: Melanoma is one of the first causes of death by cancer in the young Caucasian adult population. In light of the lack or limited efficiency of the treatments of the metastatic stages, early detection is of paramount importance since it is often a precondition to save a patient’s life by simple surgery. Dermoscopy allows the observation of the epidermis and the superficial dermis in order to significantly enhancing the diagnostic performances compared to the naked-eye examination, provided the practitioner is properly trained in this technique. Storage of the images and their comparison over time are made possible by digital dermoscopy. The present study aims at specifying the medical, psychological and socio-economic added value of dermoscopy and digital dermoscopy in terms of number of melanomas detected at a very early stage, avoidance of unnecessary surgeries and quality of life of high risk patients.

Nicolò Riggi

Title of the project:The role of microRNAs in Ewing’s sarcoma cancer stem cells.

Place of the training course: Research group of Prof. Andrew E. Rosenberg
Pathology Department at Harvard Medical School
Massachussets General Hospital (MGH)
55 Fruit Street
Boston, MA 02114

Summary of the project: Ewing’s sarcoma family tumors (ESFT), the second most common bone malignancy in children and young adults, are characterized by unique chromosomal translocations believed to provide the key oncogenic event in ESFT pathogenesis. The most common fusion gene, EWS-FLI-1, is expressed in 85-90% of ESFT and believed to represent the initiating event in ESFT development by inducing and repressing target genes that lead to transformation of permissive primary mesenchymal stem cells (MSCs), currently considered to be the most likely cell of origin of these tumors.

We have recently identified ESFT cancer stem cells and showed that they express the CD133/Prominin-1 stem cell surface marker in addition to representing the tumor initiating population of ESFT. We have subsequently shown that under appropriate culture conditions, MSC expressing EWS-FLI-1 generate a cell subpopulation displaying ESFT CSC features in vitro, and demonstrated that induction of the ESFT CSC phenotype is the result of the combined effect of EWS-FLI-1 on its target gene expression and repression of microRNA-145 (miRNA145) promoter activity. MicroRNAs are now recognized as an abundant class of genome-encoded, small RNAs that repress gene expression at the post-transcriptional level via base pairing to complementary sites located in target messenger RNAs (mRNAs). In this way a particular miRNA sequence is thought to guide the regulation of several hundred different transcripts, and, additionally, an individual mRNA may be simultaneously targeted by multiple different miRNAs. Not surprisingly therefore, miRNAs have been implicated in the regulation of a variety of diverse biological processes, and their dysregulated expression is associated with several diseases, most notably cancer.

Based on our recent observations that miRNA-145 repression underlies the emergence of ESFT CSC, we plan to further dissect the mechanisms whereby EWS-FLI-1 expression and microRNAs dysregulation lead from CSC generation to Ewing’s sarcoma development. In order to achieve this goal, in a first set of experiments, we will compare the miRNA expression profile of three primary ESFT and six different ESFT cell lines to the one of wild type MSCs. In a second set of experiments we plan to isolate CSC from freshly surgical resected ESFT samples and perform miRNA expression profile analysis of transcripts from CD133 pos. (CSC) and neg. (not-CSC) cells.

These two approaches might allow us to identify a set of miRNA whose deregulation in ESFT might constitute a crucial oncogenic mechanism in ESFT pathogenesis and that could play a significant role in ESFT CSC biology, respectively. Each putative miRNA of potential interest found to be differentially expressed will subsequently be tested individually on ESFT cell lines and primary CSC cultures to assess the impact of its modulation on their biological behaviour in vitro as well as their tumorigenic potential and CSC properties in vivo. This study will therefore provide a comprehensive overview of the involvement of miRNA in CSC generation and ESFT development. More importantly, the intrinsic ability of a single miRNA to coordinately modulate the expression of dozens of genes involved in different molecular pathways and biological processes, suggests that miRNA might constitute central nodes in the genetic circuitry of cancer, rendering them a new very attractive and promising category of therapeutic targets.

Guillaume Bergthold

Title of the project: Methylation and acetylation profiles of paediatric Low Grade Glioma (LGG)

Place of the training course: Dana Farber Cancer Institute,
450 Brookline Avenue,
Boston, MA, USA

Summary of the project: Low-grade gliomas are the most common brain tumours in children and adolescents, accounting for nearly 50% of brain tumors in this age group. From a radiological, histological and prognostic point of view, they represent a very heterogeneous group of tumours. The natural history of LGG is often unpredictable, between stability or even spontaneous regression and rapid progression like a malignant tumor. One main issue concerning the natural history of LGG is that the evolution of these tumours is highly dependent on patient age. Age less than 1 year at diagnosis was identified as a poor prognosis factor. From a structural point of view, the genome of LGG has few quantitative abnormalities. One of the ongoing emerging hypotheses suggests that epigenetic modifications are more likely to influence and modulate gene expression in tumor cells of LGG.
The profile analysis of tumour methylation and acetylation in LGG opens a new perspective in the study of their behaviour at the genomic scale. Analysis of the methylation and acetylation pattern of paediatric LGG will provide new prognostic factors, identify potential tumor suppressor genes candidates that once inhibited by methylation are involved in the carcinogenesis of these tumours and finally provide the grounds for therapeutic interventions modifying the epigenetic regulation of gene expression with demethylating agents such as 5-aza-cytidine or histone deacetylase inhibitors such as depsiptide or vorinostat (SAHA).

Marc Pusztaszeri

Title of the project: expression des microRNAs dans les léiomyosarcomes utérins

Place of the training course:Department of Pathology
Massachusetts General Hospital
Boston, USA

Summary of the project: Leiomyosarcoma is the most frequent uterine sarcoma. An accurate diagnosis is relevant, since patients diagnosed with this tumor should undergo radical hysterectomy, as mainstay of treatment. At the present time there are no consensual histologic or molecular parameters that predict behavior of this tumor, even in early stages. This tumor has a worse prognosis than most of the tumors which enter in the differential diagnosis. Therefore, there is an important need to find new markers for diagnostic, prognostic and therapeutic purposes for these tumors. The objective of this study is to analyze the expression of microRNAs in this tumor, in order find and then to validate a specific microRNA signature. This should allow us to identify new diagnostic and prognostic biomarkers and also new potential therapeutic targets for this tumor.

Dr Matthias Dettmer

Title of the project: Functional validation of microRNA expression in high-risk thyroid carcinomas

Place of the training course: University of Pittsburgh
A719 Scaife Hall
3550 Terrace Street
Pittsburgh, PA 15261
Tel: 412-864-3351
FAX: 412-802-6799

Summary of the project: Differentiated thyroid carcinomas are the most common endocrine malignancies. The 5-year survival rate is >95%. There are many known risk factors and examined prognostic markers, but as a matter of fact, it is currently not possible to predict tumor behaviour accurately. New modalities to stratify patients in the future are needed.
Many genetic alterations that drive TC have been identified during the last years. The clinical impact of most of these molecular findings is controversial discussed in the literature as studies with a large number of patients with an adverse outcome are not available.
miRNA’s are a new class of endogenous RNAs with almost countless functions in nearly every biological process, including cell cycle, apoptosis and human cancer. miRNA expression signatures have recently been detected in TC, and classifiers based on miRNA expressions are available. It has been shown that predicting tumor behaviour, based on miRNA profiling is feasible. They have been described as biomarkers as well as predictors in determining tumor aggressiveness and the probability of response to different treatment modalities. The role of miRNA in metastasization of TC is unknown, but there is increasing evidence that miRNA’s are also involved in this part of cancer progression.
Currently, we examine a well characterized collective of TC patients including a large number of patients with an adverse outcome in the lab of Prof. Nikiforov in Pittsburgh, USA and in the lab of Prof. Perren in Berne. This patient collective could be gathered thanks to collaborations with all departments of nuclear medicine and the institutes of pathology of the Canton Zurich. In our grant extension, we propose to characterize a subset of miRNA’s which play a fundamental role in thyroid cancer progression and metastasation. This subset will be identified in the currently running miRNA expression array experiments.
These functional analyses, performed in the lab of Prof. Nikiforov, a leading laboratory of thyroid tumor genetics worldwide bears the potential to fundamentally improve our understanding in the molecular alterations and miRNA expression of TC pathology. It will enlighten our knowledge how highly alternated miRNA’s interact in thyroid cancer and help understanding which target genes are involved in miRNA pathways and how. This new knowledge will eventually help to identify new therapeutic targets and understand their molecular background. Finally, clinicians and pathologists will together be able to stratify patients better and optimize their treatment. After a second year in the Pittsburgh lab, I plan to move back to Switzerland and to pursue my research track working on TC carcinogenesis, in collaboration with Pittsburgh and Bern.