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The E3 ligase Cbl-b acts on TAM tyrosine kinase receptors and has a critical role in the regulation of natural killer (NK) cell rejection of metastatic tumours; a small molecule TAM kinase inhibitor is shown to enhance the anti-metastatic NK cell activity. Controlling NK cell anti-metastatic activity This study describes a previously unknown role for the E3 ubiquitin ligase Cbl-b as part of a regulatory pathway in innate natural killer (NK) cells that licenses them to spontaneously reject cancer metastases. Genetic loss of Cbl-b or inactivation of its E3 ligase activity in mice allows NK cells to suppress growth of both multiple primary tumours and distant tumour metastases. The effect is mediated via members of the TAM family tyrosine kinase receptors, and treatment of wild-type NK cells with a small-molecule TAM inhibitor conferred therapeutic NK cell activity against metastatic melanomas. This suggests a possible approach for NK-cell-based anti-metastatic therapy in humans and at the same time explains the anti-metastatic properties of the widely used anticoagulant warfarin. Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy 1 . New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies 2 . Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity in vivo . Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology 3 . This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a ‘pill’ that awakens the innate immune system to kill cancer metastases.

Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti‐angiogenic treatment has limited efficacy due to therapy‐induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy‐induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid‐derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti‐angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor‐induced metastases, and high Apelin levels correlate with poor prognosis of anti‐angiogenic therapy patients. These data identify a druggable anti‐angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases. Synopsis Apelin is an angiogenic peptide implicated in embryonic and tumor angiogenesis. This study highlights Apelin targeting as a cancer therapy alone or in combination with current anti‐angiogenic therapies to reduce tumour growth and improve vessel structure and functionality, and thus survival. Apelin deficiency reduced tumour growth and vessel number but improved vessel function. Apelin deficiency led to a remodelling of the tumour microenvironment by altering immune cell infiltration. Combining Apelin inhibition with the anti‐angiogenic therapy Sunitinib markedly reduced tumour growth and improved survival in breast and lung cancer models. Combinatorial therapy reduced intratumoral vessel numbers compared with single treatments, but simultaneously improved blood vessel pericyte coverage, reduced hypoxia in the tumour microenvironment and prevented Sunitinib‐induced metastasis. Graphical Abstract Apelin is an angiogenic peptide implicated in embryonic and tumor angiogenesis. This study highlights Apelin targeting as a cancer therapy alone or in combination with current anti‐angiogenic therapies to reduce tumour growth and improve vessel structure and functionality, and thus survival.

Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a KrasG12D-driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif-deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of KrasG12D-driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif-knockout KrasG12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.

Nucleosomes can be modified by replacing the core histones with variants, the most diverse of which is macroH2A. The localization of macroH2A variants in human male pluripotent cells indicates that this variant functions in repression of key developmental genes and is essential for zebrafish embryogenesis. The histone variants macroH2A1 and macroH2A2 are associated with X chromosome inactivation in female mammals. However, the physiological function of macroH2A proteins on autosomes is poorly understood. Microarray-based analysis in human male pluripotent cells uncovered occupancy of both macroH2A variants at many genes encoding key regulators of development and cell fate decisions. On these genes, the presence of macroH2A1+2 is a repressive mark that overlaps locally and functionally with Polycomb repressive complex 2. We demonstrate that macroH2A1+2 contribute to the fine-tuning of temporal activation of HOXA cluster genes during neuronal differentiation. Furthermore, elimination of macroH2A2 function in zebrafish embryos produced severe but specific phenotypes. Taken together, our data demonstrate that macroH2A variants constitute an important epigenetic mark involved in the concerted regulation of gene expression programs during cellular differentiation and vertebrate development.

Successful pregnancies rely on adaptations within the mother 1 , including marked changes within the immune system 2 . It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy 3 . However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK 4 , 5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a ) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T reg ) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T reg cells through RANK in a manner that depends on AIRE + medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T reg cells during pregnancy, and expand the functional role of maternal T reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes.

Successful pregnancies rely on adaptations within the mother.sup.1, including marked changes within the immune system.sup.2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy.sup.3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK.sup.4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T.sub.reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T.sub.reg cells through RANK in a manner that depends on AIRE.sup.+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T.sub.reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T.sub.reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T.sub.reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T.sub.reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T.sub.reg cells during pregnancy, and expand the functional role of maternal T.sub.reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

Successful pregnancies rely on adaptations within the mother.sup.1, including marked changes within the immune system.sup.2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy.sup.3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK.sup.4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T.sub.reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T.sub.reg cells through RANK in a manner that depends on AIRE.sup.+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T.sub.reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T.sub.reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T.sub.reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T.sub.reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T.sub.reg cells during pregnancy, and expand the functional role of maternal T.sub.reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

Successful pregnancies rely on adaptations within the mother.sup.1, including marked changes within the immune system.sup.2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy.sup.3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK.sup.4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T.sub.reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T.sub.reg cells through RANK in a manner that depends on AIRE.sup.+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T.sub.reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T.sub.reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T.sub.reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T.sub.reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T.sub.reg cells during pregnancy, and expand the functional role of maternal T.sub.reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

Breast cancer is the most common female cancer, affecting approximately one in eight women during their life- time. Besides environmental triggers and hormones, inherited mutations in the breast cancer 1 （BRCA1） or BRCA2 genes markedly increase the risk for the development of breast cancer. Here, using two different mouse models, we show that genetic inactivation of the key osteoclast differentiation factor RANK in the mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brcal;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brcal mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brcal;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. In addition, genome variations within the RANK locus were significantly associated with risk of developing breast cancer in women with BRCA1 mutations. Thus, RANKL/ RANK control progenitor cell expansion and tumorigenesis in inherited breast cancer. These results present a viable stratesy for the uossible prevention of breast cancer in BRCA1 mutant i~atients.

The MYC proto-oncogene modulates transcription through binding to E-boxes. Di Croce and colleagues find that PAK-2-mediated phosphorylation confers a tumour-suppressive function to MYC, in which MYC cooperates with differentiation signals to positively modulate the transcription of genes targeted by retinoic acid, independently of E-boxes. MYC proto-oncogene is a key player in cell homeostasis that is commonly deregulated in human carcinogenesis 1 . MYC can either activate or repress target genes by forming a complex with MAX (ref.  2 ). MYC also exerts MAX-independent functions that are not yet fully characterized 3 . Cells possess an intrinsic pathway that can abrogate MYC–MAX dimerization and E-box interaction, by inducing phosphorylation of MYC in a PAK2-dependent manner at three residues located in its helix–loop–helix domain 4 . Here we show that these carboxy-terminal phosphorylation events switch MYC from an oncogenic to a tumour-suppressive function. In undifferentiated cells, MYC–MAX is targeted to the promoters of retinoic-acid-responsive genes by its direct interaction with the retinoic acid receptor-α (RARα). MYC–MAX cooperates with RARα to repress genes required for differentiation, in an E-box-independent manner. Conversely, on C-terminal phosphorylation of MYC during differentiation, the complex switches from a repressive to an activating function, by releasing MAX and recruiting transcriptional co-activators. Phospho-MYC synergizes with retinoic acid to eliminate circulating leukaemic cells and to decrease the level of tumour invasion. Our results identify an E-box-independent mechanism for transcriptional regulation by MYC that unveils previously unknown functions for MYC in differentiation. These may be exploited to develop alternative targeted therapies.