Molecular oncology

Keywords: genetics, epigenetics, bladder carcinoma, ERBB2, KIT, FLT3, EGFR, large-scale analysis

Our team aims to identify genes potentially involved in carcinoma tumour progression, to validate their functional properties in vitro and in vivo, to study the genetic and epigenetic mechanisms responsible for their activation or inactivation and to characterise their associated signalling pathways.
To identify candidate genes, we employ two distinct strategies: an approach targeting groups of proteins that may play a role in tumour progression and a large-scale biology approach (analysis of transcriptome and genome data generated using DNA chip technology).

Fig. 1 

Targeted approach

We have focused our work on receptor tyrosine kinases. Indeed, on the one hand these receptors are frequently implicated in tumour progression and, on the other hand, a number of examples have shown that they are particularly promising therapeutic targets (ERBB2 in breast cancer, KIT in gastrointestinal stromal tumours, FLT3 in acute lymphoblastic leukaemia, EGFR in small cell lung cancer and colon cancer).

Large-scale approach

Optimum exploitation of transcriptome and genome data, along with their integration with anatomoclinical and biological data, require the use of new tools.

Fig. 2 

In collaboration with the Bioinformatics platform, the Biostatistics department and the LIPN Bioinformatics team (University of Paris 13), we are developing new tools intended to allow:

• efficient identification of genes expressed differentially between two sample groups, taking tumour heterogeneity into account,
• the search for transcription factors responsible for the uncontrolled expression observed in cancer,
• identification of the rules of association amongst parameters of a molecular (mutations, DNA methylation, etc.), clinical (relapse times, etc.) or anatomoclinical nature and transcriptome or genome data
• inclusion, into the tumour transcriptome and genome study, of the ever increasing knowledge of signalling pathways,

Choice of cancers studied

We have chose, to study bladder carcinomas for several reasons:

• this cancer is of high medical significance. It is a frequently occurring cancer (fourth cancer in men, seventh in women) with frequent relapses after treatment,
• bladder carcinoma is well-suited to transcriptome and genome studies as tumour samples are relatively homogeneous and contain large numbers of cancer cells, thus avoiding micro-dissection steps. Furthermore, pure normal tissue (urothelium), with no underlying stroma, can be obtained for easy comparison between normal and transformed cells,
• our bladder carcinoma study, initiated by Prof. Dominique Chopin, is conducted in close collaboration with several Urology and Anatomical pathology departments of the Henri Mondor Hospital in Créteil (coordinated by Dr. Yves Allory) and the Foch Hospital in Paris (coordinated by Prof. Thierry Lebret),
• a significant proportion of human bladder carcinomas are caused by carcinogens. The existence of chemo-induced murine models enables us to analyse in vivo the involvement of candidate genes in tumour progression.

Fig. 3 

The methods used to study bladder carcinomas are then applied to two cancers both treated and studied at the Institut Curie: breast carcinomas (in collaboration with the breast thematic group within the Institut Curie) and cervical carcinomas (in collaboration with the tumour biology department).

Clinical applications

The starting point of our research is based on the study of molecular alterations in human tumours. Although our primary goal is fundamental research (advancing knowledge of the various steps in tumour progression), it is clear that the results of our work may have applications in the field of cancer, in both diagnostic, prognostic and therapeutic terms. For example, our discovery of the high rate of FGFR3 mutations in bladder tumours has many potential applications that are currently under evaluation. Thanks to our close collaboration with clinicians and anatomical pathologists, we are able to rapidly check our working hypotheses with immunohistochemical, in situ hybridization, or FISH methods conducted on a large number of samples. This collaborative work enables the transfer of fundamental research results to a clinical setting and also allows new fundamental research issues to be posed.
In the context of the CIT programme, funded and developed by the Ligue Contre le Cancer (French cancer research foundation), we are attempting to determine the aggressiveness parameters of high-grade superficial tumours (TaG3 and TIG3) and of T2-4 invasive tumours. Following identification of a tumour aggressiveness signature combining the transcriptome and genome alteration data of 200 bladder tumours, this signature is validated by immunohistochemical and FISH methods on TMAs (tissue micro-arrays) containing 500 tumours for which clinical data are available (this project involves the Henri Mondor and Foch hospitals, the Gustave Roussy Institute, the LIPN, the Ligue CIT3 team and the Institut Curie).

Ongoing projects

We have identified several new genes involved in bladder and breast cancers and coding for proteins that are potential therapeutic targets (such as PPAPDC1B phosphatase). We are currently characterising these genes and their associated signalling pathways.
The combined study of transcriptome and genome has enabled us to identify a new epigenetic mechanism in cancer. Up until very recently, the inactivation of tumour suppressor genes was considered to be the focal event leading to the extinction of isolated genes. We have been able to demonstrate that entire chromosomal regions can be inactivated by epigenetic mechanisms. For each of these regions, we characterise the epigenetic mechanisms responsible for inactivation, along with the tumour suppressor genes that they contain.

Last update: February 2009

Key publications

2008

• Bernard-Pierrot I, Gruel N, Stransky N, Vincent-Salomon A, Reyal F, Raynal V, Vallot C, Pierron G, Radvanyi F, Delattre O.
  Characterization of the recurrent 8p11-12 amplicon identifies PPAPDC1B, a phosphatase protein, as a new therapeutic target in breast cancer
  Cancer Research, 68, 7165-7175 - Full version

2007

• Elati M., Neuvial P., Bolotin-Fukuhara M., Barillot E., Radvanyi F. and Rouveirol C.
  LICORN: learning cooperative regulation networks from gene expression data
  Bioinformatics, 23, 2407-2414

2006

• Stransky N.*, Vallot C.*, Reyal F., Bernard-Pierrot I., Gil Diez de Medina S., Segraves R., de Rycke Y., Elvin P., Cassidy A., Spraggon C., Graham A., Southgate J., Asselain B., Allory Y., Abbou C.C., Albertson D.G., Thiery J.P., Chopin D.K., Pinkel D., Radvanyi F.
  *Contribution équivalente.
  Regional DNA copy number-independent deregulation of transcription in cancer
  Nature Genetics, 38, 1386 - 1396
• Nicolle G., Daher D., Maillé P., Vermey M., Loric S., Bakkar A., Wallerand H., Vordos D., Vacherot F., Gil Diez de Medina S., Abbou C.C., Van der Kwast T., Thiery J.P., Radvanyi F. and Chopin D.
  Gefitinib Inhibits the Growth and Invasion of Urothelial Carcinoma Cell Lines in which Akt and MAPK Activation is Dependent on Constitutive EGFR Activation
  Clinical Cancer Research, 12, 2937-2943
• Rouveirol C., Stransky N., Hupé P., La Rosa P., Viara E., Barillot E. and Radvanyi F.
  Computation of recurrent minimal genomic alterations from array-CGH data
  Bioinformatics, 22, 849-856