Cell polarity, Signaling and Cancer
At a glance
More than 90% of adult cancers arise from the malignant transformation of epithelial cells that normally shape organs such as breast and colon. Molecular events that alter the normal function of specific human genes, the so-called oncogenes and tumors suppressor genes, lead to impaired morphology and behavior of epithelial tissues that become tumoral and acquire novel functions such as the capacity to invade other tissues. Dissemination of cancer cells in the human body is a deadly event hardly tackled by the current therapeutic strategies. More research is therefore needed to explore new avenues able to prevent cancer dissemination.
Our multidisciplinary team studies the metastatic process at the tissue, cellular and molecular levels with the ultimate goal to identify novel therapeutic targets amenable to future treatments. We focus on solid tumors of epithelial origin such as breast and colon cancer, as well as on leukemia that, similarly to solid tumors, develop aggressive molecular characteristics.
Deciphering the basic mechanisms of epithelial differentiation is not only essential to understand normal physiology, but also crucial to improve our knowledge on the mechanisms of deregulation of cell adhesion, migration and polarity in cancers. We are currently pursuing the study of major playors of cell polarity at the organism, cellular and molecular levels, combining fundamental and transitional research in strong collaboration with clinicians, and a stimulating network of national and international collaborations.
Genetic programs required for cell adhesion, cell migration, and cell polarity occurring during epithelial differentiation are driven by secreted ligands and receptors, as well as intracellular networks of signaling and architectural molecules. Deciphering the basic mechanisms of epithelial differentiation is not only essential to understand normal physiology, but importantly, it also improves our knowledge of how deregulation of these pathways leads to abnormal cell adhesion, migration and polarity - hallmarks of diseases such as cancers.
Some of the most prominent features of carcinoma are a higher resistance to apoptosis, a loss of the polarized cyto-architecture, and the acquisition of a motile phenotype. A large body of work has already revealed determinant molecules for the fate of epithelial cells and, in some cases, has shed light on their role in cancer. This is particularly the case for the study of components of cell polarity which has contributed important information on key proteins such as the tumor suppressors E-cadherin and LKB1, and more recently, the Scribble protein complex.
When we started the lab ten years ago, we were the first to identify Erbin, a basolateral scaffold protein containing a PDZ domain, for its interaction with the ErbB2 tyrosine kinase receptor.
Since then, we have extended our interest to Erbin homologues, - Scribble and Lano -, and contributed to the characterization of these basolateral proteins in epithelial cells. For example, we first depicted biochemically and functionally the Scribble complex that comprises GEF and GAP proteins involved in cell migration. We are currently pursuing our investigations on Erbin and Scribble at the physiological and physiopathological levels using in vitro studies,- in particular state-of-the-art proteomics and functional cellular assays -, and mouse models.
We also recently became interested in the tumor suppressor LKB1 as well as in PTK7 and Vangl2, two cell polarity receptors genetically linked to Scribble. These receptors are known to participate in planar cell polarity (PCP) and are overexpressed in certain cancers.
We are currently studying the role of these polarity proteins in signal transduction and tumorigenicity.
From the beginning, our group has had a general interest in the discovery of new PDZ networks, especially when these are involved in cancer development and dissemination. We recently cloned all PDZ domain sequences in C. elegans and human in collaboration with Jérôme Reboul. These resources are easily accessible for large screens to identify novel PDZ interactions by two hybrid in yeast and other systems, and represent a good start to unravel into the ‘PDZome’.
Overall, our fundamental research is done in strong collaboration with the clinical and biopathology departments of Institut Paoli-Calmettes, and is embedded in a very fruitful and stimulating network of national and international collaborations.
About the team leader
- Aix-Marseille University, PharmD | 1995
- Aix-Marseille University, PhD | 1995
- Howard Hughes Medical Institute, Post-doc| 1995-1998
- 1995-1998 : Research Fellow, Howard Hughes Medical Institute, Ann Arbor, MI, USA
- 1998-2006 : Senior Inserm Investigator, CRCM, Marseille, France
- 2007-present : Scientific Director of Institut Paoli-Calmettes, Marseille, France
- 2006-present : Professor of Cell Biology, Aix-Marseille University
- 2012 : PU-PH, Director of CRCM
- First cloning of Erbin (ErbB2 interacting), a gene encoding a protein containing LRR and PDZ domains (Nat. Cell Biol. 2000)
- First identification of a signaling complex ßPIX-GIT1 associated to the Scribble tumor suppressor (Curr Biol 2004)
- In collaboration with Martin Schwartz’s team, first demonstration that LKB1 is an adherens junction-associated protein regulated by E-cadherin engagement (Curr Biol 2009)
- First characterization of PTK7 overexpression in acute myeloid leukemia and correlation of this event to poor prognosis (Blood 2010)
- First characterization of PTK7 implication in Wnt/ß-catenin canonical signaling (EMBO Reports 2011)
- First purification of the endogenous Vangl1/Vangl2 heteromeric complex (PLoS One 2012)
From left to right: Borg Jean-Paul, Sebbagh Michael, Axelle Garcia, Colombe Saillard, Wilfried Traore, Sebastien Martinez, Eric Bailly, Anne-Catherine Lhoumeau, Avais Daulat, Marie-Josée Santoni, Alexandre Drezet, Sylvie Marchetto, et Tania Guenneau-Puvirajesinghe.
AMIDEX BIOCLOAK Project
Tania Guenneau-Puvirajesinghe, a post doctoral fellow in Jean-Paul Borg's team, is the coordinator of an AMIDEX interdisciplinary project aiming to design a drug delivery system which can conceive a drug with concentric layers of graphene and pegylation, which provides a cloaking effect to prevent diffusion, and also physical barriers to vulnerable to enzymatic degradation and macrophage clean-up in the transporting environment of the bloodstream, thereby increasing the potency of the delivery drug molecule to the target site.