CV Science

Thierry Massfelder PhD Molecular and Cellular Pharmacology, Research Director in INSERM

Course and current status

Diplômas - Education

- Authorization to supervise research (HDR, “Habilitation à Diriger des Recherches”), April 29^th 2003.

- University Diploma: “Scientific manager in animal experimentation”, 2001, ULP

- PhD in Molecular and Cellular Pharmacology, ULP, Strasbourg, FRANCE, 1994

Formations in france and other countries

- Postdoctoral Fellow, Renal Cellular Physiology Laboratory, Department of Physiology, ULP, Strasbourg, FRANCE, 1994-1995. Director: Dr JJ HELWIG, Research Director in INSERM

- Postdoctoral Fellow, Membranes Laboratory, Department of Physiology, Ruprecht-Karls University, Heidelberg, GERMANY, 1994-1995. Director: Prof. Dr. Dr. h. c. Michael STEINHAUSEN

- Postdoctoral Associate, Department of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT, USA, 1995-1997. Director: Prof. AF. Stewart

- Research Associate, Department of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA, USA, 1997-august 1998. Director: Prof. AF. Stewart

Current position

Research Director in INSERM

UMR_S U682 INSERM/Strasbourg University

Team 3 leader "Kidney cancer and renal physiopathology" 

11, rue Humann, Bât 3, 8ème étage                             Tel: 03 68 85 34 56

67085 Strasbourg Cedex                                             Fax: 03 68 85 34 59

Scientific summary

Clear cell renal cell carcinoma (CCC) is resistant to the current targeted therapies. The von Hippel-Lindau (VHL) tumor suppressor gene, which is involved in the degradation of hypoxia-induced factors alpha (HIF), is inactivated in around 70% of CCC leading to the expression of proliferative, anti-apoptotic, metabolic and angiogenic factors such as VEGF, PDGF, TGFs and Glut-1 transporter.

We have shown that the PI3K/Akt and NF-kB pathways are oncogenic in human CCC; interestingly these pathways are also involved during nephrogenesis. Along with the results of other investigators showing the involvement of additional nephrogenic pathways and markers such as the Notch or Wnt pathways and the Pax2 transcription factor in human kidney tumorigenesis, it became clear that similarities do exist between tumorigenesis and nephrogenesis. We have recently shown that the nephrogenic (and more generally developmental) sonic hedgehog (SHH)-Gli pathway is reactivated and oncogenic in human CCC. Specifically, we have shown that this pathway is crucial for CCC growth, that it participates in the activation of for example the PI3K/Akt and NF-kB pathways and that it can be inhibited by vitamin D3 which target the Smo receptor, one of the two receptor systems of the SHH-Gli pathway. We have identified various Gli targets in human CCC including Gli itself, cyclin D1, Pax2 and the Lim1 transcription factor, an important player during nephrogenesis, that we have more recently identified as a new oncogene in this pathology, affecting tumor growth in vitro and in vivo. Our preliminary studies also revealed the SHH-Gli pathway and Lim1 may play critical role in tumor cell invasion. These results were obtained independently on the VHL status of the tumors. 

Our current research is following two complementary axes that are the role (i) of the SHH-Gli pathway and (ii) of the Lim1 transcription factor in advanced human CCC.

The first axis will be pursued by early clinical phases that we are developing along with the Urology and the Oncology departments of the Strasbourg University Hospital using vitamin D3.

The second axis has two objectives (i) to assess the effects of Lim1 on cell movements and on the expression of proteins involved in cell invasion in vitro (cadherins, MMPs, fibronectin, tenascin, chemokines …) and (ii) to study the invasive potential of Lim1 in vivo. For this second objective, two experimental approaches will be followed. The first approach will be handled using the CCC xenografted nude mice model with orthotopic implantation (under the renal capsule) of tumorigenic cell lines. For this we will use an original system with tumor cells stably transfected with two vectors, one encoding luciferase for imagery analysis of the primary tumor and metastasis and the other one encoding an inducible anti-Lim1 shRNA allowing to shut-down Lim1 expression in a time-dependent manner. This approach is designed to get insight into the potential involvement of Lim1 in tumor invasion using calibrated experimental approach. However, to develop tools usable in clinic we will also use a second experimental approach based on innovative RNA formulation in collaboration with chemists (Dr JS Rémy’s group) in Strasbourg. We will particularly search for delivery systems that are stable in human plasma and that could be developed as tool for clinical applications. Current siRNAs formulations do not give good results in vivo. The project is based on the recent promising results obtained by the team of JS Remy with new nanometric systems - photopolymerizable micelles with long plasma life duration. Since Lim1 is present only in discrete parts of the brain and thymus in the adult, this approach should be safe, as observed in mice.

In addition to these research axis we are developing innovative preclinical models in onco-urology (kidney, bladder and prostate cancers) by xenografting freshly harvested patient’s tumors in nude mice; this topic led to the creation of the spin-off Urolead (Pr H. Lang, Dr T. Massfelder, co-founders). These models will also be used for studying the involvement of Lim1 in tumor invasion using the innovative RNA formulation that we will developed according to the second research axis depicted above.

Our studies should allow the development of innovative therapeutic approaches for human CCC, a real problem of public health, characterized by a high degree of intrinsic and therapy-induced resistance. These research themes are still poorly developed worldwide. Our active collaborations with clinical departments clearly argument our wish of clinical application.