Apoptosis, cancer and develoment
Objectives
The team originally described a cell biology notion where some transmembrane receptors in some specific settings have a dual signaling ability depending on ligand accessibility : when bound to their ligand they induce various « positive » signaling pathways, whereas they induce an active signal of cell death in the absence of their ligand. These receptors were named dependence receptors as their presence at the cell surface leads the cell to be dependent for its survival on the presence of the ligand. The team currently works on three approaches: (1) deciphering in depth the molecular mechanisms of dependence receptor-induced cell death; (2) implicating these pairs receptor/ligand in tumor progression and tumor plasticity; (3) translating the basic knowledge on these pairs receptor/ligand into anti-tumor therapeutic approaches.
Projects
Our team is originally known for its work on the called dependence receptors: whereas the classic dogma postulates that transmembrane receptors are inactive unless bound by their specific ligand, it was proposed that some receptors may be active not only in the presence of their ligand, but also in their absence. In this latter case, the signaling downstream of these unbound receptors leads to apoptosis. These receptors were consequently named “dependence receptors”, as their cell expression renders the cell’s survival dependent on the presence in the cell environment of its respective ligand (Mehlen et al., 1998, Nature). To date, Patrick Mehlen and his group have identified or have been involved in the identification of most known dependence receptors.
Beyond the basic interest of studying a receptor capable of transducing two antagonizing signals –i.e., one “positive” in the presence of ligand leading to cell differentiation, proliferation or migration and one “negative” in the absence of ligand leading to cell suicide-, our group has proposed that this dual function could lead these receptors to have key roles both during embryonic development and in the regulation of tumorigenesis.
In the context of their involvement in embryonic development, we hypothesized that the pro-apoptotic activity of these dependence receptors is crucial for the development of the nervous system as a mechanism to “authorize” neuronal guidance, migration or localization in settings of ligand presence. Along this line, our group found that the Sonic Hedgehog (Shh) receptor Patched is a dependence receptor and its ability to induce apoptosis in the absence of Shh is crucial for the adequate development of the neural tube (Thibert et al., 2003, Science, Mille et al., 2009, Nat Cell. Biol.). We also showed that the netrin-1 receptors DCC and UNC5H regulate death/survival of specific neurons during the development of the nervous system (Furne et al., 2008, PNAS; Tang et al., 2008, Nat. Cell. Biol.). This implication is not limited to the developing nervous system as our group showed the importance of the apoptosis induced by UNC5H in the formation of blood vessels – angiogenesis- (Castets et al., 2009, Dev Cell.; Guenebeaud et al., 2010, Mol Cell.) or in pluripotency (Ozmadenci et al., Nat. Comm, 2015).
In the context of cancer, the hypothesis of our group is that these receptors are tumor suppressors that would limit tumor progression by inducing apoptosis of tumor cells outside of settings of ligand accessibility/availability (Mehlen and Puisieux, 2006, Nat. Rev. Cancer; Mehlen al., 2011, Nat Rev. Cancer). Our group is particularly interested in the receptors that bind netrin-1 –i.e., DCC and UNC5H-. We showed that both DCC and UNC5H are dependence receptors in cancer cells: whereas in the presence of their ligand netrin-1, they transduce “positive” signals, in the absence of netrin-1, they actively trigger apoptosis (Mehlen et al., 1998, Nature; Corset et al., 2000, Nature; Forcet et al., 2002, Nature; Llambi et al., 2001, EMBO J.; Llambi et al., 2005, EMBO J.; Dominici et al., 2017, Nature; Lengrand et al., 2023, Nature). Interestingly, DCC and UNC5H were initially considered as tumor suppressors because their expression is lost in many cancers (Thiebault et al., 2003, PNAS), suggesting that these receptors expression is a constraint for tumor progression. This was actually formally proven by showing that in mice UNC5H3 invalidation, netrin-1 up-regulation in the digestive tract or the specific inactivation of the pro-apoptotic activity of DCC resulted, in agreement with the dependence receptors paradigm, in a similar tumorigenesis (Mazelin et al., 2004, Nature; Bernet et al., 2007, Gastroenterology; Castets et al., 2012, Nature). Thus, aggressive cancers that develop are cancers for which the dependence receptor pathways are blocked through mechanisms including the genetic loss of these receptors.
However, a loss of dependence receptors is not always the selective advantage used by tumor cells to escape this survival dependence on the presence of the ligand. Indeed, our group showed that in the vast majority of human cancers, tumor cells acquire the preferred autocrine expression of netrin-1. This selective advantage for the tumor is much more appealing in terms of putative therapeutic strategy. Indeed, the titration of the ligand by a molecule that interferes with the interaction between a dependence receptor and its ligand should lead to tumor cell death. Along this line, our group showed that titration of netrin-1 by a drug candidate allows tumor cell death in vitro and triggers regression of tumors and metastases in mice (Fitamant et al., 2008, PNAS; Delloye et al. 2009a, JNCI; Delloye et al. 2009b, JEM). Of interest, this gain of ligand is probably not limited to netrin-1 but may possibly be extended to the other ligands of other dependence receptors such as NT-3, Jagged-1, SCF or SHH (Bouzas et al., JCI, 2010; Lin et al., Nat Comm, 2017; Wang et al., Mol Cell, 2018; Bissey et al., Cancer Res, 2020). Over the last past years, our group has been trying to develop drugs based on the interference on the interaction between dependence receptors and their ligands as anti-cancer strategies. A monoclonal antibody NP137 targeting netrin-1/dependence receptors interaction has been developed and has demonstrated preclinical activity (Grandin et al., Cancer Cell, 2016; Lengrand et al., Nature, 2023, EMBO MM 2016). This antibody was recently tested in a phase I trial sponsored by Centre Léon Bérard and is showing promising signs of activity (Cassier et al., Nature, 2023) and supports the ongoing phase Ib/II trials (NCT04652076, NCT05546879, NCT05546853, NCT05605496). Thus, from a basic cell biology concept, our laboratory may, within the next few years, provide new tools to fight against cancer with a wide societal impact.
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Patrick MEHLEN
patrick.mehlen@lyon.unicancer.fr
04 78 78 28 70Cheney B – 5ème étage
Centre Léon Bérard