Molecular pathology can be defined as the integration of molecular, genomic (pan genomic or DNA and RNA in situ hybridation) and transcriptomic analytical techniques with the in situ analytical tools (morphological and phenotypic) of tumour tissue to propose the most precise diagnostics or to identify and characterise new tumour entities.
Molecular pathogenesis describes a more mechanistic view of cancer with the aim of identifying biomarkers, unravelling the mechanisms of tumour initiation, progression and spreading as well as investigating the determinants of treatment resistance.
From the gene to the cell
1) Genetic biomarkers and therapeutic target identification
Project coordinated by Dr Emmanuel Barillot (IC) and Dr Olivier Delattre (Inserm / IC)
This project aims at capitalising on next-generation sequencing approaches to identify new genetic tumour markers and therapeutic targets. It encompasses the setup of experimental conditions for sequencing approaches as well as the development of appropriate bioinformatics pipeline for analyses on tumours including:
- Uveal melanoma
- Pediatric tumours, neuroblastoma in particular
- Breast cancers
- Cervical cancers
- Sarcomas, particularly Ewing sarcoma
This project relies on the state of the art next generation sequencing platform, installed in the frame of the ICGex Grant (Institut Curie Genomic of Excellence) obtained as part of the “investissement d’avenir” (investment for the future) program established by the French government and managed by the National Agency for Research (ANR-10-EQPX-03).
2) Assessing epigenomic signatures and epimutations
Project coordinated by Prof Edith Heard (Collège de France / IC) and Dr Geneviève Almouzni (CNRS / IC)
Epigenetics concerns heritable changes in genome function that are not caused by changes in the DNA sequence. Recent studies have focused on chromatin marks (DNA methylation, histone variants, post-translational modifications of histones, and non-coding RNAs), and on chromatin regulators (histone chaperones, histone variants, histone modifying enzymes, and chromatin remodelers) as critical parameters.
Many of these changes are at the heart of development biology and are also crucial for genome stability, DNA repair processes, and proper chromosome inheritance during cell division. Perturbations of chromatin factors have been associated with developmental abnormalities and disease states such as human cancer.
This project is currently investigating the following 4 themes :
- Altered chromatin regulatory machinery including histone chaperones and histone variants (Dr G Almouzni), gene silencing mechanisms via Polycomb group proteins (Dr R Margueron, Inserm / IC) and DNA methylation (Dr D Bourc’his, Inserm / IC)
- Regional epigenetic changes (Dr F Radvanyi, CNRS / IC)
- The prevalence of epimutations affecting tumour suppressors or oncogenes (Dr MH Stern, Inserm / IC)
- X-chromosome inactivation as a way to monitor epigenetic changes (Pr E Heard)
3) Molecular pathology of tumour microenvironment
Project coordinated by Dr Fatima Mechta-Grigoriou (Inserm / IC) and Dr Vassili Soumelis (IC)
The overall objective of this project is to unravel the complexity of the stromal compartment in order to understand its link with physiopathologic tumour characteristics and patient diagnosis.
Specific objectives are:
- to isolate each cell type making up the tumoural microenvironment
- to analyse the functional characteristics of the TME
- to define the networks and molecular interactions between the different cellular TME components
- to identify the role that different TME components play in tumoural development
- to define the relationship between stromal and clinical parameters
Promising therapeutic strategies
- Results of the feasibility part of the SHIVA trial (Le Tourneau et al, BJC, 2014)
- Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers (Mechta Grigoriou et al. Autophagy 2014)
- Comparative study of the frequency of ALK mutations in neuroblastoma at relapse and diagnosis. Subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse (Schleiermacher et al, J Clin Oncol 2014)
Diagnostic and prognostic markers
- Identification of a new subtype of bone sarcoma (Pierron et al, Nat Genetics, 2012)
- Integrated analysis of genetic variations in Ewing sarcoma. The complete sequencing of more than 100 patients’ genome was carried out in the frame of the ICGC consortium. Recurrent STAG2, CDKN2A and TP53 mutations as well as epigenetic markers were identified. Significant correlations were made with the clinical data. (Tirode et al, Cancer Discovery, 2014)
- The chromatin regulator HJURP is an independent prognostic marker for luminal A breast carcinoma (Montes de Oca, 2014)
- Characterisation of rearrangements involving the ALK gene reveals a novel truncated form associated with tumour aggressiveness in neuroblastoma (Cazes et al, Cancer Res, 2013).
Basic research and methodological approaches
- Breakpoint features of genomic rearrangements in neuroblastoma with unbalanced translocations and chromothripsis (Boeva et al, Plos One, 2013)
- Demonstration that SF3B1 is frequently mutated in uveal melanoma and the mutation is associated with an alternative splicing of aberrant (Furney et al, Cancer Discovery, 2013)
- Use of chromatin markers and X chromosome genes to evaluate the epigenetic changes in the prognostic or diagnostic context (Chaligné et al, FEBS Letters, 2014)
- Setting up of an innovative system-level approach associating mathematical and data-driven analysis allowing resolution of the theoretical and experimental diversity of interactions in the integration process through which cells sense and compute the response to external stimuli (Soumelis et al, Nature Commun, 2015)
- Development of new methodologies for copy number alteration detection for targeted or genome wide analysis (Boeva et al, Bioinformatics, 2014; Boeva et al, Bioinformatics, 2012)
- High-resolution 3D DNA FISH using plasmid probes and computational correction of optical aberrations to study chromatin structure at the sub-megabase (Giorgetti et al, Methods Mol Biol, 2015)