Our research work focuses on the contribution of post-transcriptional mechanisms on cancer cell adaptation, in particular RNA epigenetic & translational control. Following decades of near-dormancy, these fields are experiencing a rebirth, mostly thanks to recent progress in detection techniques such as high throughput sequencing and mass spectrometry. Within the framework of the S.M.A.R.T. consortium, we are implementing unique tools and techniques to produce innovative research at the crossroads of basic, applied and clinical science.
Our group is involved in 3 main axis of research, each of them covering a specific area of interest, from basic to clinical research:
EpiTransDiag, that seeks to analyze RNA modification signatures from patient samples for diagnosis and/or prognosis purpose.
ScOre, whose goal is to study RNA epigenetic effectors involved in cancer evolution and develop small molecules-based inhibitors for therapeutic use.
GEM, a collaborative effort that associates the modelling capacity of biophysics to large scale and genome wide analyses of bioinformatics to solve major questions regarding the post-transcriptional control of gene expression.
Cancer Stem Cells – the roots of resistance, metastasis and relapse. Despite significant advances in diagnostics and therapeutic treatment, colorectal cancer (CRC) remains a major cause of mortality and morbidity worldwide. This is due to the fact that CRC survival is highly dependent upon stage of disease at diagnosis: though early stage shows 70 to 90% 5-year survival, once the tumor spreads out to distant organs, 5-year survival plummets toward 10%. Metastasis is a multistep process encompassing local infiltration of tumor cells into adjacent tissues, transendothelial migration into vessels, survival in the circulatory system, extravasation, and colonization of secondary organs. Overall, this process entails step-by-step reprogramming of gene expression and necessitates tremendous adaptation capability, a specific trait of cancer stem cells (CSC). CSC represents a minor subpopulation of tumor cells endowed with self-renewal and multi-lineage differentiation capacity. Moreover, they can escape from chemotherapies, disseminate and re-create a full-fledged tumor in inhospitable distant tissue environment. Understanding the molecular mechanisms that bestow CSC adaptation ability is a major goal to design new therapeutic strategies that may prevent both tumor relapse and metastasis formation, which coincides with poor prognosis and increased mortality.
Post-transcriptional control and cell adaptation. Transcriptional control alone cannot suffice neither to achieve the remarkable spatial deployment of proteins observed in every cell, nor to provide a highly dynamic temporal response in case of stress. Post-transcriptional mechanisms, and most particularly translational control, play a crucial role in adaptation mechanisms. This concept is emphasized by several studies showing that only 20-40% of variability of protein levels can be accredited to mRNA levels in mammalian cells. This disconnection between transcriptome and proteome suggests that all mRNAs are not equal in term of translation efficiency according to the cellular needs. In particular, dynamic chemical modifications in RNA affect transcript fate by altering base pairing potential, secondary structure and protein-RNA interactions. In turn, these physical properties modulate RNA processing, localization, translation, and decay. A such, epitranscriptomic code plays a key role in the outcome of gene expression. In this context, transcriptomic analyses alone become inadequate to comprehend cellular events. A deeper understanding of post-transcriptional mechanisms is required as well as large scale identification of mRNAs actively engaged in the translation machinery, also referred as “translatome”.