Polycomb Regulates NF-κB Signaling in Cancer through miRNA

The mechanisms leading to the constitutive activation of NF-κB in cancers and the pathways upstream and downstream of this activation are not fully understood. In this issue of Cancer Cell, Yamagishi et al. demonstrate that Polycomb-mediated silencing of miR-31 is implicated in the aberrant activation of NF-κB signaling in tumors

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy

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

Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy

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 inhibitorinduced 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

Regulatory mechanisms of c-Myc and their role in Acute Myeloid Leukemia

The c-Myc transcription factor is a key player in cell homeostasis, being commonly deregulated in human carcinogenesis. In this PhD thesis we have addressed the question how regulatory mechanisms restrain the oncogenic activity of c-Myc and its impact on cell differentiation. In the first half, we report that PML promotes destabilization of c-Myc protein and re-activation of c-Myc-repressed target genes. The consequent re-expression of the cell cycle inhibitor CDKN1A/p21 mediates differentiation of leukemic cells. In the second half of the thesis we identified a novel mechanism of gene regulation by c-Myc, which is mediated through its interaction with DNA-bound RARα. In undifferentiated cells, c-Myc/Max dimers cooperate with RARα in the repression of genes required for differentiation. Upon phosphorylation of c-Myc by the previously identified Pak2, the complex switches from a repressive to an activating function by releasing Max and recruiting transcriptional coactivators. These findings add a new and at least partially Max-independent mechanism for transcriptional regulation by c-Myc and also discover an unexpected function of c-Myc in inhibiting and promoting cellular differentiation. Taken together, our results describe two new mechanisms that counteract the oncogenic activity of c-Myc. Both PML and Pak2 can be considered as tumor suppressors since they modulate c-Myc function in a way that ultimately promotes differentiation of leukemic cells. This knowledge provides the basis for novel approaches to be exploited for the development of c-Myc-targeted therapies.El factor de transcripció c-Myc juga un paper clau en l’homeòstasi cel·lular, essent freqüentment desregulat en la carcinogènesi humana. En aquesta tesi s’ha estudiat com diferents mecanismes reguladors poden frenar l’activitat oncogènica de c-Myc i el subsegüent impacte en la diferenciació cel·lular. A la primera meitat de la tesi, es demostra que PML promou la desestabilització de la proteïna c-Myc i, en conseqüència, la reactivació dels genes diana reprimits per c-Myc. Entre aquests gens diana es troba l’inhibidor del cicle cel·lular CDKN1A/p21, la reexpressió del qual provoca la diferenciació de cèl·lules leucèmiques induïda per PML. En la segona meitat, s’identifica un nou mecanisme de regulació transcripcional per part de c-Myc a través de la interacció amb RARα, el qual està unit a l’ADN. En cèl·lules indiferenciades, els dimers c-Myc/Max cooperen amb RARα en la repressió de gens essencials per a la diferenciació. Un cop c-Myc és fosforil·lat per la kinasa Pak2, el complex de c-Myc amb RARα esdevé activador mitjançant la pèrdua de Max i el reclutament de coactivadors transcripcionals. Aquest descobriment suposa un nou mecanisme mitjançant el qual c-Myc pot exercicir la regulació gènica almenys en part independentment de Max, i també revela una funció desconeguda de c-Myc en la inhibició i promoció de la diferenciació cel·lular. En conjunt, aquests resultats descriuen dos nous mecanismes que contrarestren l’activitat oncogènica de c-Myc. PML i Pak2 poden ser considerats supressors de tumors ja que modulen la funció de c-Myc per a promoure la diferenciació de les cèl·lules leucèmiques. Aquests descobriments poden utilitzar-se com a base pel desenvolupament de noves teràpies anti-tumorals que tinguin com a diana la proteïna c-Myc

The histone variant macroH2A is an epigenetic regulator of key developmental genes

The histone variants macroH2A1 1 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.Peer Reviewe

RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy

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 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 and depletion of Rank in the thymic epithelium results in reduced accumulation of natural T(reg) cells in the placenta, accompanied by an increased number of miscarriages. Thymic deletion of Rank also resulted in impaired accumulation of T(reg) cells in visceral adipose tissue, associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis; key hallmarks of gestational diabetes. Transplantation of T(reg) cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, 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 gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis

The Tumor Suppressor Hace1 Is a Critical Regulator of TNFR1-Mediated Cell Fate

The HECT domain E3 ligase HACE1 has been identified as a tumor suppressor in multiple cancers. Here, we report that HACE1 is a central gatekeeper of TNFR1-induced cell fate. Genetic inactivation of HACE1 inhibits TNF-stimulated NF-κB activation and TNFR1-NF-κB-dependent pathogen clearance in vivo. Moreover, TNF-induced apoptosis was impaired in hace1 mutant cells and knockout mice in vivo. Mechanistically, HACE1 is essential for the ubiquitylation of the adaptor protein TRAF2 and formation of the apoptotic caspase-8 effector complex. Intriguingly, loss of HACE1 does not impair TNFR1-mediated necroptotic cell fate via RIP1 and RIP3 kinases. Loss of HACE1 predisposes animals to colonic inflammation and carcinogenesis in vivo, which is markedly alleviated by genetic inactivation of RIP3 kinase and TNFR1. Thus, HACE1 controls TNF-elicited cell fate decisions and exerts tumor suppressor and anti-inflammatory activities via a TNFR1-RIP3 kinase-necroptosis pathway

RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer

Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer

RANKL/RANK control Brca1 mutation- .

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 Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological inhibition of the RANK ligand RANKL in mice abolished the occurrence of Brca1 mutation-driven pre-neoplastic lesions. Mechanistically, genetic inactivation of Rank or RANKL/RANK blockade impaired proliferation and expansion of both murine Brca1;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 strategy for the possible prevention of breast cancer in BRCA1 mutant patients