Our team has a long-lasting expertise in the signaling field in cancer by working for several decades on two oncogenic families: the RAF Ser/Thr kinases (Peyssonnaux and Eychene, Biol Cell 2001) and the MAF transcription factors (Eychene et al., Nat Rev Cancer 2008). We have made major contributions by identifying and cloning a member of each of these two families (Benkhelifa et al., Oncogene 1998; Marx et al., EMBO 1988). We also deciphered their mechanisms of regulation including those by phosphorylation (Benkhelifa et al., Mol Cell Biol 2001; Hmitou et al., Mol Cell Biol 2007; Rocques et al., Mol Cell 2007; Herath et al., Blood Cancer J 2014).
Our studies have progressively led us to focus our interest on two types of cancers in which these families play a key role: MEDULLOBLASTOMA and MELANOMA.
Our current projects focus on deregulated signaling pathways and transcription factors involved in the initiation and progression of these two pathologies and their mechanisms of resistance to treatments.
Medulloblastoma (MB) is the most common malignant brain tumor of childhood arising in the cerebellum. Although multimodal treatments have significantly increased the survival rate, 20-30% of patients remain incurable. Most of them belong to a poorly characterized MB subgroup, called group 3 (G3), which displays unexpected expression of a retina photoreceptor-specific differentiation program. This defines an aberrant retinal identity to this tumor unrelated to the cerebellum where it originates. We demonstrated that NRL, a MAF family member, established this aberrant identity and, importantly, is required for tumor maintenance by promoting proliferation and protecting medulloblastoma cells from apoptosis (Garancher et al., Cancer Cell 2018). This work extends the concept of lineage addiction in cancer by showing that an aberrant identity characterized by a lineage unrelated to the tissue of origin could represent a dependency.
We also showed that pharmacological agents targeting anti-apoptotic proteins display interesting therapeutic potential for group 3 MB.
We are currently working on deregulated signaling pathways and transcription factors in the poorly characterized G3 MB as well as on the mechanisms of resistance to radiotherapy.
Melanoma, one of the deadliest skin cancers, is mainly driven by deregulation of the RAS/RAF/MEK/ERK pathway due in about 50% of cases to mutations in the BRAF gene and in 15% in NRAS.
We have developed different genetic mouse models to evaluate the specific contributions of the different RAF kinases during normal and pathological melanocytic lineage development. We demonstrated that RAF/MAPK signaling is dispensable for early melanocyte lineage development but required for melanocyte stem cell self-maintenance (Valluet et al., Cell reports 2012), thereby providing the first in vivo demonstration that RAF proteins can be involved in stemness.
We also used these knockouts to investigate the role of both RAF kinases in NRASQ61K-induced melanoma at each step of tumor progression, from initiation (benign nevi formation) to invasive melanoma (Dorard et al., Nat Commun. 2017). We showed that BRAF has a critical role in initiation of NRAS-driven melanoma that cannot be compensated by CRAF. In contrast, RAF proteins display compensatory functions in full-blown tumors and ARAF can sustain proliferation in the absence of BRAF and CRAF, highlighting an addiction to RAF signaling in NRAS-driven melanoma (Druillennec et al., Mol Cell Oncol. 2017).
We are currently investigating the molecular mechanisms underlying the contribution of the three RAF kinases in melanoma progression and resistance to treatments.