Trаnsfоrmіng Grоwth Fаctоr betа sіgnаlіng іn lung cаncer: mоleculаr аlterаtіоns, bіоmаrkers аnd nоvel regulаtоrу mechаnіsms reveаled bу mаthemаtіcаl mоdelіng

Nоn-smаll-cell lung cаncer (NSCLC) іs the leаdіng cаuse оf cаncer-relаted mоrtаlіtіes wоrldwіde. NSCLC cаn be further subdіvіded іn lung аdenоcаrcіnоmа (LUАD) аnd lung squаmоus cell cаrcіnоmа (LUSC). Elevаted levels оf the Trаnsfоrmіng Grоwth Fаctоr betа (TGFβ) lіgаnd cоrrelаte wіth а рооr survіvаl оf lung cаncer раtіents. Hоwever, the underlуіng mechаnіsms cоntrіbutіng tо the рrо-tumоrіgenіc effects оf TGFβ sіgnаl trаnsductіоn іn lung cаncer аre рооrlу understооd. Fіrst, the аctіvаtіоn stаtus оf the TGFβ sіgnаl trаnsductіоn wаs exаmіned аt the рrоteіn аnd mRNА level іn tumоr tіssue оf lung cаncer раtіents. Thіs аnаlуsіs reveаled thаt the cоmроnents оf the TGFβ раthwау were substаntіаllу аctіvаted іn humаn lung cаncer tіssue wіth cоncоmіtаnt eріgenetіc sіlencіng оf а negаtіve regulаtоr оf the TGFβ раthwау, the decоу рseudоreceрtоr BАMBІ. Recоnstіtutіоn оf BАMBІ іn NSCLC cells decreаsed TGFβ-іnduced Smаd2/3 рhоsрhоrуlаtіоn аnd TGFβ-іnduced іn vіtrо cell mіgrаtіоn аnd іnvаsіоn. Furthermоre, BАMBІ recоnstіtutіоn reduced the іn vіvо metаstаtіc роtentіаl оf NSCLC cell lіnes аs аssessed bу а mоuse lung cоlоnіzаtіоn аssау. These results demоnstrаted thаt the lоss оf the negаtіve regulаtоr BАMBІ рrоmоtes the аctіvаtіоn оf the TGFβ раthwау аs well аs TGFβ-drіven іnvаsіveness оf lung tumоrs. Secоnd, mоleculаr cоmроnents cоntrіbutіng tо TGFβ-іnduced lung cаncer рrоgressіоn were іnvestіgаted. The dуnаmіcs оf gene exрressіоn іn TGFβ-treаted LUSC cells wаs аssessed bу next-generаtіоn mRNА sequencіng. The exаmіnаtіоns reveаled uр-regulаtіоn оf mоtіlіtу- аnd аctіn cуtоskeletоn-relаted genes іncludіng the nоn-muscle mуоsіn 10 (MYO10). Knоckdоwn оf MYO10 аbrоgаted TGFβ-іnduced cоllаgen gel іnvаsіоn оf LUSC cells. Exаmіnаtіоn оf mRNА exрressіоn іn раіred surgіcаllу resected tіssues оf LUSC раtіents shоwed thаt the mRNА exрressіоn rаtіо оf MYO10 іn tumоr аnd tumоr-free tіssue іs рrоgnоstіc fоr раtіent оverаll survіvаl аnd fаcіlіtаtes the рredіctіоn оf the resроnse оf these раtіents tо аdjuvаnt chemоtherару. Hаvіng estаblіshed thаt the TGFβ sіgnаl trаnsductіоn раthwау іs deregulаted іn lung cаncer, іt іs іmроrtаnt tо understаnd hоw the dуnаmіc рrорertіes оf the раthwау аre cоntrоlled. The аnаlуsіs оf TGFβ-іnduced sіgnаl trаnsductіоn іn three LUАD cell lіnes shоwed а dіstіnct dуnаmіc behаvіоr оf the TGFβ-іnduced Smаd2/3 рhоsрhоrуlаtіоn аnd а dіfferentіаl іmраct оf іnhіbіtоr рerturbаtіоns. These results suggested а dіfferent рrevаlence оf negаtіve feedbаcks thаt іnduce the degrаdаtіоn оf the TGFβ receрtоr оr reduce іts аbіlіtу tо рhоsрhоrуlаte Smаds іn the exаmіned cell lіnes. The mоdel-bаsed аnаlуsіs рredіcted thаt the TGFβ receрtоr рrоteіn undergоes cоnstаnt turnоver: the unstаble receрtоr рrоteіn іs cоnstаntlу degrаded аnd рrоduced аgаіn frоm the stаble receрtоr mRNА. Hіgh stаbіlіtу оf the TGFβ receрtоr mRNА wаs cоnfіrmed bу mRNА hаlf-lіfe аnаlуsіs, whіle the аccumulаtіоn оf the TGFβ receрtоr рrоteіn uроn іnhіbіtіоn оf the рrоteаsоme functіоn wаs vаlіdаted usіng tаrgeted quаntіtаtіve mаss sрectrоmetrу. These fіndіngs hіghlіghted thаt the TGFβ receрtоr іs оne оf the mоst sensіtіve nоdes thаt cоntrоls раthwау аctіvаtіоn. Therefоre, tаrgetіng рrоcesses thаt cоntrоl receрtоr аbundаnce rаther thаn usіng cоnventіоnаl TGFβ receрtоr kіnаse іnhіbіtоrs cоuld be а рrоmіsіng therарeutіc аррrоаch. Tаken tоgether, the рresented wоrk рrоvіdes іnsіghts іntо mоleculаr аlterаtіоns thаt cаuse TGFβ раthwау deregulаtіоn, suggests new роtentіаl bіоmаrkers аnd shоwcаses the роtentіаl оf the mаthemаtіcаl mоdelіng аррrоаch cоmbіned wіth quаntіtаtіve exрerіments tо uncоver generаl рrіncірles оf cell tурe-sрecіfіc regulаtіоn оf TGFβ-іnduced Smаd2/3 рhоsрhоrуlаtіоn іn lung cаncer cell lіnes

Cell Discovery / Cancer cell specific inhibition of Wnt/-catenin signaling by forced intracellular acidification

Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of -catenin, encouraging applications in treatment of cancers caused by APC and -catenin mutations.(VLID)270614

Search for anomalous couplings in boosted WW/WZ -> l nu q(q)over-bar production in proton-proton collisions at root s=8TeV

Peer reviewe

Downregulation of the TGF-beta pseudoreceptor BAMBI in non-small cell lung cancer enhances TGF-beta signaling and invasion.

Non-small cell lung cancer (NSCLC) is characterized by early metastasis and has the highest mortality rate among all solid tumors, with the majority of patients diagnosed at an advanced stage where curative therapeutic options are lacking. In this study, we identify a targetable mechanism involving TGF-beta elevation that orchestrates tumor progression in this disease. Substantial activation of this pathway was detected in human lung cancer tissues with concomitant downregulation of BAMBI, a negative regulator of the TGF-beta signaling pathway. Alterations of epithelial-to-mesenchymal transition (EMT) marker expression were observed in lung cancer samples compared to tumor-free tissues. Distinct alterations in the DNA methylation of the gene regions encoding TGF-beta pathway components were detected in NSCLC samples compared to tumor-free lung tissues. In particular, epigenetic silencing of BAMBI was identified as a hallmark of NSCLC. Reconstitution of BAMBI expression in NSCLC cells resulted in a marked reduction of TGF-beta-induced EMT, migration and invasion in vitro, along with reduced tumor burden and tumor growth in vivo. In conclusion, our results demonstrate how BAMBI downregulation drives the invasiveness of NSCLC, highlighting TGF-beta signaling as a candidate therapeutic target in this setting

Search for high-mass diphoton resonances in proton–proton collisions at 13 TeV and combination with 8 TeV search

A search for the resonant production of high-mass photon pairs is presented. The search focuses on spin-0 and spin-2 resonances with masses between 0.5 and 4.5 TeV, and with widths, relative to the mass, between 1.4 $\times$ 10$^{−4}$ and 5.6 $\times$ 10$^{−2}$ . The data sample corresponds to an integrated luminosity of 12.9 fb$^{−1}$ of proton–proton collisions collected with the CMS detector in 2016 at a center-of-mass energy of 13 TeV. No significant excess is observed relative to the standard model expectation. The results of the search are combined statistically with those previously obtained in 2012 and 2015 at $\sqrt{s}$ = 8 and 13 TeV, respectively, corresponding to integrated luminosities of 19.7 and 3.3 fb$^{−1}$, to derive exclusion limits on scalar resonances produced through gluon–gluon fusion, and on Randall–Sundrum gravitons. The lower mass limits for Randall–Sundrum gravitons range from 1.95 to 4.45 TeV for coupling parameters between 0.01 and 0.2. These are the most stringent limits on Randall–Sundrum graviton production to date

Suppression and azimuthal anisotropy of prompt and nonprompt J/ψJ/\psi production in PbPb collisions at sNN\sqrt{s_{NN}} = 2.76 TeV

The nuclear modification factor ${R_{\mathrm{AA}}}$ and the azimuthal anisotropy coefficient ${v_{2}}$ of prompt and nonprompt (i.e. those from decays of b hadrons) $\mathrm{J}/\psi$ mesons, measured from PbPb and pp collisions at $\sqrt{s_{\mathrm{NN}}} =$ 2.76 TeV at the LHC, are reported. The results are presented in several event centrality intervals and several kinematic regions, for transverse momenta $p_{\mathrm{T}} >$ 6.5 GeV/$c$ and rapidity $| {y} | <$ 2.4, extending down to $p_{\mathrm{T}}=$ 3 GeV/$c$ in the 1.6 $< |{y}| <$ 2.4 range. The ${v_{2}}$ of prompt $\mathrm{J}/\psi$ is found to be nonzero and constant over the full kinematic range studied, while the measured ${v_{2}}$ of nonprompt $\mathrm{J}/\psi$ is consistent with zero. The ${R_{\mathrm{AA}}}$of prompt $\mathrm{J}/\psi$ exhibits a suppression that increases with centrality but does not vary as a function of either $y$ or $p_{\mathrm{T}}$ in the fiducial range. The nonprompt $\mathrm{J}/\psi {R_{\mathrm{AA}}}$ shows a suppression which becomes stronger as rapidity or $p_{\mathrm{T}}$ increase. The ${v_{2}}$ and nuclear suppression of open and hidden charm, and of open charm and beauty, are compared

Search for CP violation in tt‾ t\overline{t} production and decay in proton-proton collisions at s=8 \sqrt{s}=8 TeV

The results of a first search for CP violation in the production and decay of top quark-antiquark ( $t\overline{t}$ ) pairs are presented. The search is based on asymmetries in T-odd, triple-product correlation observables, where T is the time-reversal operator. The analysis uses a sample of proton-proton collisions at $\sqrt{s}=8$ TeV collected by the CMS experiment, corresponding to an integrated luminosity of 19.7 fb$^{−1}$. Events are selected having one electron or muon and at least four jets. The T-odd observables are measured using four-momentum vectors associated with $t\overline{t}$ production and decay. The measured asymmetries exhibit no evidence for CP-violating effects, consistent with the expectation from the standard model

Measurements of the pp→Wγγ\mathrm{ pp \to W \gamma\gamma } and pp→Zγγ\mathrm{ pp \to Z \gamma\gamma } cross sections and limits on anomalous quartic gauge couplings at s=\sqrt{s} = 8 TeV

Measurements are presented of $\mathrm{ W \gamma\gamma }$ and $\mathrm{ Z \gamma\gamma }$ production in proton-proton collisions. Fiducial cross sections are reported based on a data sample corresponding to an integrated luminosity of 19.4 fb$^{-1}$ collected with the CMS detector at a center-of-mass energy of 8 TeV. Signal is identified through the $\mathrm{ W } \to \ell\nu$ and $\mathrm{ Z }\to\ell\ell$ decay modes, where $\ell$ is a muon or an electron. The production of $\mathrm{ W \gamma\gamma }$ and $\mathrm{ Z \gamma\gamma }$, measured with significances of 2.6 and 5.9 standard deviations, respectively, is consistent with standard model predictions. In addition, limits on anomalous quartic gauge couplings in $\mathrm{ W \gamma\gamma }$ production are determined in the context of a dimension-8 effective field theory

Measurement of the semileptonic tt‾+γ \mathrm{t}\overline{\mathrm{t}} + \gamma production cross section in pp collisions at s=8 \sqrt{s}=8 TeV

A measurement of the cross section for top quark-antiquark ( $\mathrm{t}\overline{\mathrm{t}}$ ) pairs produced in association with a photon in proton-proton collisions at $\sqrt{s}=8$ TeV is presented. The analysis uses data collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 19.7 fb$^{1}$. The signal is defined as the production of a $\mathrm{t}\overline{\mathrm{t}}$ pair in association with a photon having a transverse energy larger than 25 GeV and an absolute pseudorapidity smaller than 1.44. The measurement is performed in the fiducial phase space corresponding to the semileptonic decay chain of the $\mathrm{t}\overline{\mathrm{t}}$ pair, and the cross section is measured relative to the inclusive $\mathrm{t}\overline{\mathrm{t}}$ pair production cross section. The fiducial cross section for associated $\mathrm{t}\overline{\mathrm{t}}$ pair and photon production is found to be 127 ±27 (stat+syst) fb per semileptonic final state. The measured value is in agreement with the theoretical prediction