Patrick Mehlen

Patrick Mehlen (born in 1968), is a French biologist and research director at the Centre national de recherche scientifique (CNRS) at the Centre Léon-Bérard, a cancer research centre in Lyon.[1]

Education

Patrick Mehlen, a former student at the École normale supérieure de Lyon, defended his Ph.D. thesis at the Claude-Bernard University in 1995. From 1997 to 1998 he spent two sabbatical years at the Burnham Institute for Medical Research, program on "Aging and Cell Death" - Pr. D.E. Bredesen. Back in France, he became head of the "Apoptosis and Differentiation" group in the laboratory - CNRS UMR5534, CGMC until 2004. Then he became director of the "Apoptosis, Cancer and Development" research unit - CNRS FRE2870 then UMR5238 at the Léon Bérard Centre until 2011. He joined the Lyon Cancer Research Centre, where he became the director in 2019. He is also Director of Translational Research and Innovation at the Léon Bérard Centre since 2013, Director of the DEVweCAN Laboratory of Excellence since 2011 and Director of the Rabelais Institute for Interdisciplinary Cancer Research (Convergence Institute) since 2018.

Research

Patrick Mehlen was one of the discoverers of the addictive receptor paradigm: from an original mechanism of cell death to clinical trials; explained below and which constitutes the presentation of his scientific work.

A few years ago, an original concept of cell biology was proposed: while classical dogma assumed that transmembrane receptors are inactive unless bound by their specific ligand, it was proposed that some receptors could be active not only in the presence of their ligand, but also in their absence. In the latter case, the downstream signalling of these unbound receptors leads to programmed cell death, also called apoptosis. These receptors have therefore been called "dependent receptors" because their presence on the cell surface makes the cell's survival dependent on the presence in the cell environment of its respective ligand.[2] To date, Mehlen and his collaborators have identified or participated in the identification of the most well known dependent receptors.

Beyond the fundamental interest of studying a receptor capable of transducing two antagonistic signals - a "positive" one in the presence of ligands leading to cell differentiation, proliferation or migration and a "negative" one in the absence of ligands leading to cell suicide, they proposed that this dual function could lead these receptors to play a key role both during embryonic development and in regulating tumorigenesis.

In the context of their involvement in embryonic development, they hypothesized that the pro-apoptotic activity of these dependence receptors is crucial for the development of the nervous system as a mechanism "allowing" neural guidance, migration or localization in ligand situations. Thus, they found that the Sonic Hedgehog (Shh) Patched receptor is a dependency receptor and that its ability to induce apoptosis in the absence of Shh is essential for adequate neural tube development.[3][4] They also showed that the receptors of netrin-1 DCC and UNC5H regulate the death/survival of specific neurons during the development of the nervous system.[5][6] This involvement is not limited to the developing nervous system, as they have shown the importance of UNC5H-induced apoptosis in the formation of blood vessels - angiogenesis.[7][8]

In the context of cancer, they hypothesized that these receptors are tumor suppressors that would limit cancer progression[9] by inducing apoptosis of tumor cells outside the territories of ligand accessibility/availability.[10][11] They were particularly interested in receptors that bind to the netrin-1 ligand -i.e., DCC and UNC5H-. They have shown that DCC and UNC5H are all dependency receptors in cancer cells: whereas in the presence of their netrin-1 ligand, they transduce classical "positive" signals, in the absence of netrin-1, they actively trigger apoptosis.[12][13][14][15][16][17][18] Interestingly, DCC and UNC5H are considered tumor suppressors because their expression is lost in many cancers[19][20] suggesting that the presence of these receptors is a constraint to tumor progression. This has in fact been formally proven by showing that in mice, the invalidation of UNC5H3, the overexpression of netrin-1 in the digestive tract or the specific inactivation of pro-apoptotic DCC activity similarly caused cancer progression.[21][22] Thus, aggressive cancers that develop are cancers for which tumor cells block the pathways of dependent receptors[23][24][25][26] and a mechanism for this inactivation of this cell death pathway is that tumor cells acquire an autocrine secretion of netrin-1. These researchers then showed that an agent blocking the interaction between netrin-1 and its receptors allowed in vitro to lead to the death of tumor cells and in animals to control tumor progression. With this in mind, they have generated a drug candidate - anti-netrin-1/NP137 antibody - which is currently being tested in patients with very advanced cancers with very encouraging signs of clinical activity.

Honours

Mehlen was elected in 2013 to the French Academy of sciences.[27]

References
  1. "Synergie Lyon Cancer".
  2. Mehlen P. et al., « The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis », Nature, 1998
  3. Thibert et al., « Inhibition of neuroepithelial patched-induced apoptosis by sonic hedgehog », Science, 2003
  4. Mille et al., « The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. », Nat Cell. Biol, 2009
  5. Furne et al., « Netrin-1 is a survival factor during commissural neuron navigation », PNAS, 2008
  6. Tang et al., « Netrin-1 Mediates Neuronal Survival Through PIKE-L Interaction With the Dependence Receptor UNC5B », Nat. Cell. Biol, 2008
  7. Castets et al., « Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis », Dev Cell, 2009
  8. Guenebeaud et al., « The dependence receptor UNC5H2 triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase », Mol Cell, 2010
  9. Mazelin et al., « Netrin-1 controls colorectal tumorigenesis by regulating apoptosis », Nature, 2004
  10. Mehlen et Puisieux, « Metastasis: a question of life or death. », Nat. Rev. Cancer, 2006
  11. Mehlen al., « Novel roles for Slits and netrins: axon guidance cues as anti-cancer targets? », Nat Rev. Cancer, 2011
  12. Mehlen et al., « The DCC gene product induces apoptosis by a mechanism requiring receptor proteolysis », Nature, 1998
  13. Corset et al., « Netrin-1 induced growth cone attraction and cAMP production is mediated via interaction with the Adenosine A2b receptor », Nature, 2000
  14. Forcet et al., « DCC-dependent MAPK activation is required for netrin-1 mediated axon outgrowth », Nature, 2002
  15. Llambi et al., « Netrin-1 acts as a survival factor via its receptors UNC5H and DCC », EMBO J, 2001
  16. Llambi et al., « The dependence receptor UNC5H2 mediates apoptosis through DAP kinase », EMBO J, 2005
  17. Guenbeaud et al., « The dependence receptor UNC5H2 triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase », Mol Cell, 2009
  18. Dominici et al., « Floor-plate-derived netrin-1 is dispensable for commissural axon guidance », Nature, 2017
  19. Mehlen et Gibert, « Dependence receptors and cancer: addiction to trophic ligands », Cancer Res, 2015
  20. Thiebault et al., « The netrin-1 receptors UNC5H are putative tumor suppressors controlling cell death commitment », PNAS, 2003
  21. Bernet et al., « Inactivation of the UNC5C Netrin-1 receptor is associated with tumor progression in colorectal malignancies », Gastroentérologie, 2007
  22. Castets et al., « DCC constrains tumor progression via its dependence receptor activity », Nature, 2012
  23. Fitamant et al., « Netrin-1 expression confers a selective advantage for tumor cell survival in metastatic breast cancer », PNAS, 2008
  24. Delloye et al., « Interference with Netrin-1 and Tumor Cell Death in Non–Small Cell Lung Cancer », JNCI, 2009a
  25. Delloye et al., « Netrin-1 acts as a survival factor for aggressive neuroblastoma », JEM, 2009b
  26. Broutier et al., « Targeting netrin-1/DCC interaction in Diffuse Large-B and Mantle Cell Lymphoma », EMBO MM, 2016
  27. "Académie des sciences".
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