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Content archived on 2024-06-18

A new role for CD44 in carcinogenesis

Final Report Summary - CD44 CARCINOGENESIS (A new role for CD44 in carcinogenesis)

A new role for CD44 in carcinogenesis

CD44 is a transmembrane glycoprotein highly polymorphic expressed in most tissues. CD44 represents the principal receptor for the main matrix glycosaminoglucan component, the hyaluronic acid (Ponta et al., 2003). CD44 is a multifunctional protein involved in lymphocyte homing and activation, cell migration or apoptosis. CD44 functions are modulated by metalloproteases that cleave the extracellular part of CD44, giving rise to a soluble form. The remaining transmembrane part of CD44 can be further cleaved by gamma-secretase resulting in the liberation of the C-terminus tail, called CD44ICD (intracellular domain), which translocates to the nucleus. Although, the functions of CD44ICD are not yet understood, it has been shown that it can potentiate its own transcription in a p300/CBP dependant manner (Okamoto et al., 2001). Recent work from the team has shown that CD44ICD per se possesses a transforming activity in rat cells which is actively participating in the oncogenesis induced by the oncogenic form of Ret MEN2A (multiple endocrine neoplasia type 2A, characterised by medullary carcinoma in the thyroid), revealing a new function for CD44ICD in tumourigenesis (Pelletier et al., 2006).

Based on these observations, the aim of the European Reintegration Grant (ERG) was to widen the study of cell transformation to human cells and to characterise the molecular mechanisms through which CD44ICD promotes cell transformation. To that purpose, we planned to investigate the molecular partners and the transcriptional targets of CD44ICD. In a first approach, together with a PhD student of the laboratory, Mouhannad Malek, we overexpressed different constructs of rat CD44ICD in human cells. In these human cellular systems, we were not able to detect any effect of the protein CD44ICD on the activity of several transcription factors such as NFkB, AP1 or p53 nor we were able to induce cell transformation in human immortalised mammary epithelial cells. We speculated that this absence of phenotype could be due to a species issue since we were expressing a rat protein in human cells. We therefore decided to design new expression vectors in order to overexpress human CD44ICD in human cells. Unfortunately, the human constructs we made were toxic in different human cell lines, not allowing us any study the CD44ICD human protein in cells. Beside, in order to discover the putative interactants of human CD44ICD, we also sent these constructs to a well-established company (hybrigenics) to perform a yeast-two hybrid screen. Unfortunately for us, the contructs were also toxic in the yeast and the company was not able to deliver any results. While we were performing these experiments, the team of Dr Manié was evaluated by national evaluation committees to be part of the newly created Cancer Research Center of Lyon. Unfortunately, the team was not given the authorisation to be created and we had to join other CRCL teams. Altogether these events led me to decide to start my own projects in order to obtain my own team in a near future.

As presented in the mid-term report, I decided to take advantage of this research experience in the cancer field to implement a new project based on my strong background on the inflammasome area. I started a research project aiming at understanding the role of the inflammasome in cancer entitled 'inflammation and cancer: deciphering a new role for the inflammasome in tumourigenesis'. The aim of the project is to understand at the cellular and molecular levels the impact of the inflammasome on tumour development using mouse genetic models for breast and lung cancer.

Thanks to the ERG funding, I could import a few groups of mice to perform preliminary experiments from my formal director's lab (Jurg Tschopp's lab UNIL, Switzerland). I tested whether the inflammasome is required into the tumour microenvironnement for the tumour to grow by injecting mouse mammary cancer cells (4T1 cells) into the mammary fatpad of inflammasome proficient or deficient (caspase-1 KO) mice. This preliminary experiment was really encouraging since the tumour cells formed much smaller tumours in the inflammasome deficient mice compared with wild-type animals. I obtained other groups of mice to perform additional experiments and trained a Master student on this project. These preliminary data encouraged me to import the inflammasome deficient mice into our mouse facility and to apply to a junior group leader position package at INSERM/CNRS. I obtained the ATIP/AVENIR position within the CRCL and started officially in January 2012 as a Junior Group Leader. The funding is EUR 300 000 for 3 years.

To conclude, the Marie Curie ERG was a crucial support for my career as it gave me financial independence to attend two international meetings on cancer, to train a student on my project and to start over a new project when the hosting team was closed down. Thus, I consider the ERG programme as a key support to young scientists returning from postdoctoral training.