EZH2-Mediated Primary Cilium Deconstruction Drives Metastatic Melanoma Formation.

Human melanomas frequently harbor amplifications of EZH2. However, the contribution of EZH2 to melanoma formation has remained elusive. Taking advantage of murine melanoma models, we show that EZH2 drives tumorigenesis from benign BrafV600E- or NrasQ61K-expressing melanocytes by silencing of genes relevant for the integrity of the primary cilium, a signaling organelle projecting from the surface of vertebrate cells. Consequently, gain of EZH2 promotes loss of primary cilia in benign melanocytic lesions. In contrast, blockade of EZH2 activity evokes ciliogenesis and cilia-dependent growth inhibition in malignant melanoma. Finally, we demonstrate that loss of cilia enhances pro-tumorigenic WNT/ß-catenin signaling, and is itself sufficient to drive metastatic melanoma in benign cells. Thus, primary cilia deconstruction is a key process in EZH2-driven melanomagenesis.

Injury and stress responses of adult neural crest-derived cells.

Multipotent neural crest cells can self-renew and give rise to a plethora of neural and non-neural cell types in the vertebrate embryo. Intriguingly, cells reminiscent of such neural crest stem cells (NCSCs) have also been isolated from various postnatal and adult neural crest (NC)-derived structures. However, it has been debated whether NCSC-like cells in the adult correspond to 'in vitro artefacts' emerging upon isolation or fulfil a physiological role in vivo. Here, we discuss recent findings indicating that in different adult NC derivatives, injury or stress responses induce a NCSC-like state, presumably by reprogramming differentiated cells such as Schwann cells. Thereby, injury or stress appear to endow NC-derived cells with the capacity to generate new cell types during the repair process; in addition, injury can activate a repair program in adult NC-derived cells, which promotes tissue repair or regeneration by paracrine signalling. Thus, there is increasing evidence that NCSC-like cells in NC derivatives represent an in vivo state implicated in distinct physiological functions in the adult organism.

The Histone Methyltransferase Ezh2 Controls Mechanisms of Adaptive Resistance to Tumor Immunotherapy.

Immunotherapy and particularly immune checkpoint inhibitors have resulted in remarkable clinical responses in patients with immunogenic tumors, although most cancers develop resistance to immunotherapy. The molecular mechanisms of tumor resistance to immunotherapy remain poorly understood. We now show that induction of the histone methyltransferase Ezh2 controls several tumor cell-intrinsic and extrinsic resistance mechanisms. Notably, T cell infiltration selectively correlated with high EZH2-PRC2 complex activity in human skin cutaneous melanoma. During anti-CTLA-4 or IL-2 immunotherapy in mice, intratumoral tumor necrosis factor-α (TNF-α) production and T cell accumulation resulted in increased Ezh2 expression in melanoma cells, which in turn silenced their own immunogenicity and antigen presentation. Ezh2 inactivation reversed this resistance and synergized with anti-CTLA-4 and IL-2 immunotherapy to suppress melanoma growth. These anti-tumor effects depended on intratumorally accumulating interferon-γ (IFN-γ)-producing PD-1low CD8+ T cells and PD-L1 downregulation on melanoma cells. Hence, Ezh2 serves as a molecular switch controlling melanoma escape during T cell-targeting immunotherapies.

TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays.

Axon formation, the initial step in establishing neuronal polarity, critically depends on local microtubule reorganization and is characterized by the formation of parallel microtubule bundles. How uniform microtubule polarity is achieved during axonal development remains an outstanding question. Here, we show that the tripartite motif containing (TRIM) protein TRIM46 plays an instructive role in the initial polarization of neuronal cells. TRIM46 is specifically localized to the newly specified axon and, at later stages, partly overlaps with the axon initial segment (AIS). TRIM46 specifically forms closely spaced parallel microtubule bundles oriented with their plus-end out. Without TRIM46, all neurites have a dendrite-like mixed microtubule organization resulting in Tau missorting and altered cargo trafficking. By forming uniform microtubule bundles in the axon, TRIM46 is required for neuronal polarity and axon specification in vitro and in vivo. Thus, TRIM46 defines a unique axonal cytoskeletal compartment for regulating microtubule organization during neuronal development.

Ribosomal Protein Mutations Result in Constitutive p53 Protein Degradation through Impairment of the AKT Pathway.

Mutations in ribosomal protein (RP) genes can result in the loss of erythrocyte progenitor cells and cause severe anemia. This is seen in patients with Diamond-Blackfan anemia (DBA), a pure red cell aplasia and bone marrow failure syndrome that is almost exclusively linked to RP gene haploinsufficiency. While the mechanisms underlying the cytopenia phenotype of patients with these mutations are not completely understood, it is believed that stabilization of the p53 tumor suppressor protein may induce apoptosis in the progenitor cells. In stark contrast, tumor cells from zebrafish with RP gene haploinsufficiency are unable to stabilize p53 even when exposed to acute DNA damage despite transcribing wild type p53 normally. In this work we demonstrate that p53 has a limited role in eliciting the anemia phenotype of zebrafish models of DBA. In fact, we find that RP-deficient embryos exhibit the same normal p53 transcription, absence of p53 protein, and impaired p53 response to DNA damage as RP haploinsufficient tumor cells. Recently we reported that RP mutations suppress activity of the AKT pathway, and we show here that this suppression results in proteasomal degradation of p53. By re-activating the AKT pathway or by inhibiting GSK-3, a downstream modifier that normally represses AKT signaling, we are able to restore the stabilization of p53. Our work indicates that the anemia phenotype of zebrafish models of DBA is dependent on factors other than p53, and may hold clinical significance for both DBA and the increasing number of cancers revealing spontaneous mutations in RP genes.