Scientific project

 

The project of team 5 is organized in 2 axes: The first axis « Mucins in epithelial cancers » is the logical follow-up of the present research. The second axis “Mechanisms of tumor resistance and dormancy” emerges from the recent SIRIC-ONCOLille (Lille Comprehensive Cancer Research Center) label awarded by INCa (French National Cancer Institute).

The overall strategy of team 5 is to better understand the mechanisms associated with epithelial carcinogenesis, and bring new tools (diagnostic/prognostic/predictive) to the clinicians to facilitate patient care/management and propose better therapeutic approaches.

This original and ambitious project typically translational with high valorization potential aims at proposing new molecules with therapeutic value, identifying new biomarkers and new therapeutic targets necessary for prevention and early diagnostic in cancerology and especially for epithelial cancers with bad prognosis such as pancreatic cancer. This is also true for the other epithelial cancers we are working on: esophago-gastric, colorectal and renal cancers.

A. The role of mucins in epithelial cancers

In this part of the project we wish to study the in vivo role of MUC4 in pancreatic tumor progression and show its involvement in epithelial tumor interactions with its immediate environment (stroma). This will be performed thanks to the pre-clinical murine model of pancreatic cancer deficient or not for Muc4 that we have established in the laboratory. We will also study MUC1, MUC4 localisation in relation with tumor prognosis. We will study the role of galectins in mucin intracellular trafficking and mRNA stability. We will also study MUC1 nuclear translocation and try to decipher the mechanisms responsible for MUC1 cytoplasmic tail (MUC1-CT) processing at the membrane and the consequences for the cancer cell.

B. Mechanisms associated with tumor resistance to loco-regional treatments and tumor dormancy

These projects are part of the two scientific programs of ONCOLille SIRIC (program #1: tumor resistance and program #2: tumor dormancy).

B.1. MUC4 and chemoresistance. Having shown that MUC4 plays a role in PC cell resistance to gemcitabine, we want to see whether this role is general and also true for other drugs used to treat patients with PDAC and especially those of the FOLFIRINOX protocol (5-FU, oxaliplatine and SN-38/irinotecan).

B.2. Esophago-gastric cancers. The work on esophageal cancer will be extended to squamous cell carcinoma (SCC) of the esophagus, an excess-incidence and mortality esophageal cancer in the Nord-Pas de Calais region. We will create a xenografted model in SCID mice with SCC cells. Those experiments will allow us to obtain a preclinical animal model to analyse the differential response to potential therapeutic targets between SRC and non-SRC tumors. Tissue micro arrays (TMA) will be made in a selected population of resected patients (EA and SCC) with or without preoperative treatment. These TMAs will be used to test potential biomarkers that could be identified during further experiments. The same approach will be used to study signet ring cell gastric carcinoma (SRC) versus non SRC. In this project, we wish to compare in vitro and in vivo the chemosensitivity of SRC and non-SRC cell lines to usual chemotherapy drugs such as 5-FU, epirubicin, and ciplatinum.

B.3. Tumor dormancy. In this project we want to decipher the mechanisms associated with entry into dormancy of chemoresistant cancer cells. We will study the c-Yes-mediated signalling pathways in the regulation of YAP activity both in cells exposed to 5-FU genotoxic stress and cells cultured 5-FU-free conditions.

B.4. Importance of epigenetic modifications in the cancer stem cell/cancer cell transition. In this part of the project we will identify the epigenetic profiles accompanying normal cell differentiation and carcinogenesis by using next generation sequencing (NGS) technology. We will also use cell-sorting technologies to isolate normal and cancer stem cells and compare their epigenetic profiles with differentiated cells along the crypt-villus axis using ChIP-Seq and MeDIP-Seq technologies.

In parallel to basic science projects, we develop translational research with clinicians/biologists of the team working at the CHRU of Lille to transfer our knowledge to the clinical practice.