Generation of Immature, Mature and Tolerogenic Dendritic Cells with Differing Metabolic Phenotypes

Immune response results from a complex interplay between the antigen non-specific innate immune system and the antigen specific adaptive immune system. ...

Agency for Science, Technology and Research

Epithelial mesenchymal transition (EMT) is a fundamental mechanism controlling multiple events during embryonic development. Mesenchymal cells appear transiently in some diploblasts, the most primitive species characterized by two epithelial layers. Since almost 800 million years, EMT has been conserved throughout evolution to control morphogenetic events, such as the formation of the three primary germ layers during gastrulation. Most interestingly, specific molecular pathways have been conserved in many different species to drive EMT. In the animal kingdom, a recurrent theme is that EMT controls the intercellular adhesion machinery and the dynamics of its associated cytoskeleton. EMT pathways are also tightly connected to determination and differentiation programs, and are reactivated in adult tissues following injury or exposure to toxic agents. EMT is now shown to operate during the early stages of carcinoma invasion leading to blood or lymph vessel intravasation of malignant cells. The converse mechanism - mesenchymal-epithelial transition (MET) - then operates at distant sites from the primary tumor to form macrometastases from isolated micrometastatic cells. The mesenchymal-like state of carcinoma confers stemness, protection from cell death, escape from immune response and, most importantly, resistance to conventional and targeted therapies. Our laboratory has designed an EMT high-throughput screen of small molecular weight compounds and biologics in order to establish new therapeutic approaches that interfere with the plasticity of carcinoma cells. New therapeutic interventions are envisioned to delay tumor recurrence.

[Epithelial mesenchymal transition during development in fibrosis and in the progression of carcinoma].

Epithelial-mesenchymal transition (EMT) is a fundamental mechanism in development driving body plan formation. EMT describes a transition process wherein polarized epithelial cells lose their characteristics and acquire a mesenchymal phenotype. The apico-basal polarity of epithelial cells is replaced by a front-rear polarity in mesenchymal cells which favor cell-extracellular matrix than intercellular adhesion. These events serve as a prerequisite to the context-dependent migratory and invasive functions of mesenchymal cells. In solid tumors, carcinoma cells undergoing EMT not only invade and metastasize but also exhibit cancer stem cell-like properties, providing resistance to conventional and targeted therapies. In cardiovascular systems, epicardial cells engaged in EMT contribute to myocardial regeneration. Conversely, cardiovascular endothelial cells undergoing EMT cause cardiac fibrosis. Growing evidence has shed light on the potential development of novel therapeutics that target cell movement by applying the EMT concept, and this may provide new therapeutic strategies for the treatment of cancer and heart diseases.

Target cell movement in tumor and cardiovascular diseases based on the epithelial-mesenchymal transition concept.

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&#x95F4;&#x5145;&#x8D28;&#x7EC6;&#x80DE;&#x8F6C;&#x548C;&#x764C;&#x7EC6;&#x80DE;&#x7684;&#x4F20;&#x64AD;&#x662F;&#x7531;&#x9AD3;&#x7EC6;&#x80DE;&#x6E90;&#x6027;&#x6291;&#x764C;&#x7EC6;&#x80DE;&#x6D78;&#x6DA6;&#x539F;&#x53D1;&#x6027;&#x80BF;&#x7624;&#x9A71;&#x52A8;&#x7684;&#x3002;

In order to metastasize, cancer cells need to acquire a motile phenotype. Previously, development of this phenotype was thought to rely on the acquisition of selected, random mutations and thus would occur late in cancer progression. However, recent studies show that cancer cells disseminate early, implying the existence of a different, faster route to the metastatic motile phenotype. Using a spontaneous murine model of melanoma, we show that a subset of bone marrow-derived immune cells (myeloid-derived suppressor cells or MDSC) preferentially infiltrates the primary tumor and actively promotes cancer cell dissemination by inducing epithelial-mesenchymal transition (EMT). CXCL5 is the main chemokine attracting MDSC to the primary tumor. In vitro assay using purified MDSC showed that TGF-Î², EGF, and HGF signaling pathways are all used by MDSC to induce EMT in cancer cells. These findings explain how cancer cells acquire a motile phenotype so early and provide a mechanistic explanation for the long recognized link between inflammation and cancer progression.

Mesenchymal transition and dissemination of cancer cells is driven by myeloid-derived suppressor cells infiltrating the primary tumor.

Pour m&eacute;tastaser, cellules canc&eacute;reuses doivent acqu&eacute;rir un ph&eacute;notype motile. Auparavant, mise au point de ce ph&eacute;notype &eacute;tait cens&eacute;e s&#39;appuyer sur l&#39;acquisition de certaines mutations al&eacute;atoires et donc aurait lieu vers la fin de la progression du cancer. Toutefois, des &eacute;tudes r&eacute;centes montrent que les cellules canc&eacute;reuses diffuser d&egrave;s le d&eacute;but, ce qui implique l&#39;existence d&#39;un itin&eacute;raire diff&eacute;rent, plus rapide pour le ph&eacute;notype motile m&eacute;tastatique. &Agrave; l&#39;aide d&#39;un mod&egrave;le murin spontan&eacute; du m&eacute;lanome, nous montrons qu&#39;un sous-ensemble de la moelle osseuse des cellules immunitaires (cellules suppressives my&eacute;lo&iuml;de d&eacute;riv&eacute;es ou MDSC) pr&eacute;f&eacute;rentiellement s&#39;infiltre dans la tumeur primitive et promeut activement la diffusion cellulaire du cancer en induisant la transition &eacute;pith&eacute;liale-m&eacute;senchymateuse (EMT). CXCL5 est le principal chimiokines attirant MDSC &agrave; la tumeur primitive. Test in vitro &agrave; l&#39;aide de MDSC purifi&eacute;e a montr&eacute; que les voies de signalisation TGF-&beta;, EGF et HGF sont tous utilis&eacute;s par MDSC pour induire des EMT dans les cellules canc&eacute;reuses. Ces r&eacute;sultats expliquent comment les cellules canc&eacute;reuses acqui&egrave;rent un ph&eacute;notype motile si t&ocirc;t et fournissent une explication m&eacute;caniste pour le lien reconnu depuis longtemps entre la progression de l&#39;inflammation et le cancer.

Transition m&eacute;senchymateuse et la diss&eacute;mination des cellules canc&eacute;reuses est entra&icirc;n&eacute;e par les cellules my&eacute;lo&iuml;des d&eacute;riv&eacute;s suppresseur infiltrant la tumeur primitive.

Um metastasieren, m&uuml;ssen Krebszellen einen st&auml;bchenf&ouml;rmiges Ph&auml;notyp zu erwerben. Zuvor, Entwicklung von diesem Ph&auml;notyp auf den Erwerb von ausgew&auml;hlten, zuf&auml;llige Mutationen verlassen und war so sp&auml;t im Fortschreiten auftreten w&uuml;rde. Allerdings zeigen neuere Studien, dass Krebszellen fr&uuml;h verbreiten, impliziert die Existenz von eine andere, schnellere Route zu der metastasierendem st&auml;bchenf&ouml;rmiges Ph&auml;notyp. Anhand einer spontanen murinen Modell des Melanoms zeigen wir, dass eine Teilmenge der Knochenmark-abgeleitete immune Zellen (Suppressorzellen myeloide abgeleitet oder MDSC) bevorzugt den prim&auml;ren Tumor infiltriert und aktiv Krebs Zelle Verbreitung f&ouml;rdert durch epitheliale-Mesenchymale Transition (EMT) induzieren. CXCL5 ist die wichtigste Chemokine MDSC, des prim&auml;ren Tumors zieht. In vitro Tests mit gereinigtem MDSC zeigte, dass TGF-&beta;, EGF und HGF Signalwege alle MDSC nutzt, um EMT in Krebszellen induzieren. Diese Ergebnisse erkl&auml;ren, wie Krebszellen einen st&auml;bchenf&ouml;rmiges Ph&auml;notyp so fr&uuml;h zu erwerben und bieten eine mechanistische Erkl&auml;rung f&uuml;r die lange erkannten Zusammenhang zwischen Entz&uuml;ndung und Krebs Fortschreiten.

Mesenchymale Transition und Verbreitung der Krebszellen ist myeloische abgeleitete Suppressorzellen infiltrieren Prim&auml;rtumors Gefahren.

Per metastasi, cellule tumorali devono acquisire un fenotipo motili. In precedenza, lo sviluppo di questo fenotipo &egrave; stato pensato per fare affidamento sull&#39;acquisizione di mutazioni casuali, selezionate e si verificherebbe cos&igrave; tardi nella progressione del cancro. Tuttavia, studi recenti mostrano che le cellule tumorali diffondere all&#39;inizio, che implica l&#39;esistenza di un percorso diverso, pi&ugrave; veloce il fenotipo metastatico motili. Utilizzando un modello murino spontaneo del melanoma, mostriamo che un sottoinsieme delle cellule immuni (cellule mieloidi derivato soppressore o MDSC) derivate dal midollo osseo si infiltra preferenzialmente il tumore primario e promuove attivamente la diffusione delle cellule di cancro inducendo transizione epiteliale-mesenchimale (EMT). CXCL5 &egrave; la chemochina principale attirando MDSC al tumore primario. Analisi in vitro usando purificato MDSC ha mostrato che TGF-&beta;, EGF e HGF signaling pathways sono tutti utilizzati da MDSC per indurre EMT nelle cellule tumorali. Questi risultati spiegano come le cellule tumorali acquisiscono un fenotipo motili cos&igrave; presto e forniscono una spiegazione meccanicistica per il collegamento tra infiammazione e cancro progressione lungo riconosciuto.

Transizione mesenchimale e la diffusione delle cellule tumorali &egrave; guidato dalle cellule mieloidi derivato soppressore infiltranti il tumore primario.

&#x8EE2;&#x79FB;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x304C;&#x3093;&#x7D30;&#x80DE;&#x904B;&#x52D5;&#x6027;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3092;&#x53D6;&#x5F97;&#x3059;&#x308B;&#x5FC5;&#x8981;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x4EE5;&#x524D;&#x306F;&#x3001;&#x3053;&#x306E;&#x8868;&#x73FE;&#x578B;&#x306E;&#x958B;&#x767A;&#x306F;&#x9078;&#x629E;&#x3059;&#x308B;&#x3068;&#x3001;&#x30E9;&#x30F3;&#x30C0;&#x30E0;&#x306A;&#x7A81;&#x7136;&#x5909;&#x7570;&#x306E;&#x7FD2;&#x5F97;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x3068;&#x8003;&#x3048;&#x3089;&#x308C;&#x3066;&#x3044;&#x305F;&#x3001;&#x5F93;&#x3063;&#x3066;&#x764C;&#x306E;&#x9032;&#x884C;&#x3092;&#x9045;&#x304F;&#x767A;&#x751F;&#x3059;&#x308B;&#x3067;&#x3057;&#x3087;&#x3046;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;&#x6700;&#x8FD1;&#x306E;&#x7814;&#x7A76;&#x3092;&#x793A;&#x3059;&#x8EE2;&#x79FB;&#x904B;&#x52D5;&#x6027;&#x8868;&#x73FE;&#x578B;&#x3078;&#x306E;&#x5225;&#x3088;&#x308A;&#x9AD8;&#x901F;&#x306A;&#x30EB;&#x30FC;&#x30C8;&#x306E;&#x5B58;&#x5728;&#x3092;&#x610F;&#x5473;&#x3057;&#x3066;&#x304C;&#x3093;&#x7D30;&#x80DE;&#x304C;&#x65E9;&#x671F;&#x306B;&#x666E;&#x53CA;&#x3055;&#x305B;&#x308B;&#x3053;&#x3068;&#x3002;&#x60AA;&#x6027;&#x9ED2;&#x8272;&#x816B;&#x306E;&#x81EA;&#x767A;&#x7684;&#x306A;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x3001;&#x9AA8;&#x9AC4;&#x7531;&#x6765;&#x514D;&#x75AB;&#x7D30;&#x80DE; (&#x9AA8;&#x9AC4;&#x7531;&#x6765;&#x306E;&#x30B5;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x7D30;&#x80DE;&#x307E;&#x305F;&#x306F; MDSC) &#x306E;&#x30B5;&#x30D6;&#x30BB;&#x30C3;&#x30C8;&#x304C;&#x512A;&#x5148;&#x7684;&#x539F;&#x767A;&#x816B;&#x760D;&#x6D78;&#x6F64;&#x3057;&#x3001;&#x4E0A;&#x76AE;&#x9593;&#x8449;&#x8EE2;&#x63DB; &#xFF08;EMT&#xFF09; &#x306E;&#x8A98;&#x5C0E;&#x306B;&#x3088;&#x308B;&#x304C;&#x3093;&#x7D30;&#x80DE;&#x306E;&#x666E;&#x53CA;&#x3092;&#x7A4D;&#x6975;&#x7684;&#x306B;&#x63A8;&#x9032;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;CXCL5 MDSC &#x539F;&#x767A;&#x816B;&#x760D;&#x3092;&#x96C6;&#x3081;&#x3066;&#x30E1;&#x30A4;&#x30F3; &#x30B1;&#x30E2;&#x30AB;&#x30A4;&#x30F3;&#x3067;&#x3059;&#x3002;&#x7CBE;&#x88FD; MDSC &#x3092;&#x7528;&#x3044;&#x305F; in vitro &#x30A2;&#x30C3;&#x30BB;&#x30A4; TGF-&beta;, EGF, &#x304A;&#x3088;&#x3073; HGF &#x306E;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x3059;&#x3079;&#x3066; MDSC &#x306B;&#x3088;&#x3063;&#x3066;&#x764C;&#x7D30;&#x80DE;&#x306E; EMT &#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x77E5;&#x898B;&#x306F;&#x3001;&#x304C;&#x3093;&#x7D30;&#x80DE;&#x306E;&#x904B;&#x52D5;&#x6027;&#x306E;&#x8868;&#x73FE;&#x578B;&#x3092;&#x305D;&#x3093;&#x306A;&#x306B;&#x65E9;&#x304F;&#x53D6;&#x5F97;&#x3057;&#x3001;&#x9577;&#x3044;&#x8A8D;&#x8B58;&#x306E;&#x30EA;&#x30F3;&#x30AF;&#x708E;&#x75C7;&#x3068;&#x764C;&#x306E;&#x9032;&#x884C;&#x306E;&#x9593;&#x306E;&#x6A5F;&#x68B0;&#x7684;&#x306A;&#x8AAC;&#x660E;&#x3092;&#x63D0;&#x4F9B;&#x306B;&#x3064;&#x3044;&#x3066;&#x8AAC;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;

&#x9593;&#x8449;&#x8EE2;&#x63DB;&#x304A;&#x3088;&#x3073;&#x764C;&#x7D30;&#x80DE;&#x306E;&#x666E;&#x53CA;&#x306F;&#x539F;&#x767A;&#x816B;&#x760D;&#x6D78;&#x6F64;&#x9AA8;&#x9AC4;&#x7531;&#x6765;&#x306E;&#x30B5;&#x30D7;&#x30EC;&#x30C3;&#x30B5;&#x30FC;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x3063;&#x3066;&#x99C6;&#x52D5;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;

&#xC804;&#xC774;, &#xD558;&#xB824;&#xBA74; &#xC554; &#xC138;&#xD3EC; &#xC6B4;&#xB3D9; &#xD615;&#xC744; &#xD68D;&#xB4DD; &#xD574;&#xC57C; &#xD569;&#xB2C8;&#xB2E4;. &#xC774;&#xC804;&#xC5D0;,&#xC774; &#xD615;&#xC758; &#xAC1C;&#xBC1C; &#xC120;&#xD0DD;&#xD55C;, &#xBB34;&#xC791;&#xC704; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; &#xC778;&#xC218;&#xC758; &#xC9C0;&#xB97C; &#xC0DD;&#xAC01; &#xD558; &#xACE0; &#xC554; &#xC9C4;&#xD589;&#xC5D0; &#xB530;&#xB77C;&#xC11C; &#xBC1C;&#xC0DD; &#xD558;&#xB294;. &#xADF8;&#xB7EC;&#xB098;, &#xCD5C;&#xADFC; &#xD559;&#xBB38;&#xC740; &#xBCF4;&#xC5EC;&#xC900;&#xB2E4; &#xC554; &#xC138;&#xD3EC;&#xB97C; &#xC77C;&#xCC0D;, &#xC720;&#xD3EC; &#xC804;&#xC774;&#xC131; &#xBA54;&#xAD6C;&#xBBF8; &#xD45C;&#xD604; &#xD615;&#xC744; &#xB354; &#xBE68;&#xB9AC;, &#xB2E4;&#xB978; &#xACBD;&#xB85C;&#xC758; &#xC874;&#xC7AC;&#xB97C; &#xC554;&#xC2DC;. &#xD751;&#xC0C9;&#xC758; &#xC790;&#xBC1C;&#xC801;&#xC778; murine &#xBAA8;&#xB378;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC;, &#xC6B0;&#xB9AC; &#xACE8; &#xC218; &#xC720;&#xB798; &#xBA74;&#xC5ED; &#xC138;&#xD3EC; (&#xC5B5;&#xC555; &#xACE8;&#xC218;&#xC131; &#xD30C;&#xC0DD; &#xC140; &#xB610;&#xB294; MDSC)&#xC758; &#xD558;&#xC704; &#xC9D1;&#xD569; &#xC6B0;&#xC120;&#xC801;&#xC73C;&#xB85C; &#xAE30;&#xBCF8; &#xC885;&#xC591; &#xCE68;&#xD22C; &#xD558; &#xACE0; &#xC801;&#xADF9;&#xC801;&#xC73C;&#xB85C; &#xC0C1;&#xD53C; &#xC5FD; &#xC804;&#xD658; (&#xC751;&#xAE09;)&#xB97C; &#xC720;&#xB3C4; &#xD558; &#xC5EC; &#xC554; &#xC138;&#xD3EC; &#xBCF4;&#xAE09; &#xCD09;&#xC9C4;&#xC744; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. CXCL5 MDSC &#xAE30;&#xBCF8; &#xC885;&#xC591;&#xC5D0; &#xC720;&#xCE58; &#xC8FC;&#xC694; chemokine &#xC774;&#xB2E4;. &#xC815;&#xD654; MDSC&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xC0DD;&#xCCB4; &#xC678; &#xBD84;&#xC11D; &#xACB0;&#xACFC; TGF-&beta;, EGF, &#xBC0F; HGF &#xC2E0;&#xD638; &#xACBD;&#xB85C; &#xBAA8;&#xB4E0; &#xC0AC;&#xC6A9; MDSC &#xD558; &#xC5EC; &#xC554; &#xC138;&#xD3EC;&#xC5D0; &#xAD6C;&#xAE09; &#xB300;&#xB97C; &#xC720;&#xB3C4; &#xD558;&#xAE30; &#xC704;&#xD574; &#xB098;&#xD0C0;&#xB0AC;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xC554; &#xC138;&#xD3EC; &#xC6B4;&#xB3D9; &#xD615;&#xC744; &#xC77C;&#xCC0D; &#xCDE8;&#xB4DD; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xACFC; &#xAE30;&#xACC4; &#xC124;&#xBA85;&#xACFC; &#xC5FC;&#xC99D;&#xACFC; &#xC554; &#xC9C4;&#xD589; &#xAC04;&#xC758; &#xAE34; &#xC778;&#xC2DD;&#xB41C; &#xB9C1;&#xD06C;&#xC5D0; &#xB300; &#xD55C; &#xC124;&#xBA85;.

&#xC5FD; &#xC804;&#xC774; &#xBC0F; &#xC554; &#xC138;&#xD3EC;&#xC758; &#xBCF4;&#xAE09; &#xC5B5;&#xC555; &#xACE8;&#xC218;&#xC131; &#xD30C;&#xC0DD; &#xC140; &#xAE30;&#xBCF8; &#xC885;&#xC591; &#xCE68;&#xD22C;&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xB3D9; &#xB429;&#xB2C8;&#xB2E4;.

Con el fin de hacer met&aacute;stasis, las c&eacute;lulas cancerosas necesitan adquirir un fenotipo m&oacute;vil. Previamente, el desarrollo de este fenotipo pensaba contar con la adquisici&oacute;n de las mutaciones al azar y as&iacute; ocurrir&iacute;a en la progresi&oacute;n del c&aacute;ncer. Sin embargo, estudios recientes muestran que las c&eacute;lulas cancerosas difusi&oacute;n temprano, lo que implica la existencia de una ruta diferente, m&aacute;s r&aacute;pida al fenotipo metast&aacute;sico m&oacute;vil. Utilizando un modelo murino espont&aacute;neo del melanoma, demostramos que un subconjunto de c&eacute;lulas inmunes de m&eacute;dula &oacute;sea (c&eacute;lulas supresoras mieloides derivados o MDSC) preferentemente infiltra el tumor primario y promueve activamente la difusi&oacute;n de la c&eacute;lula de c&aacute;ncer induciendo la transici&oacute;n epitelial-mesenquimal (EMT). CXCL5 es la Quimiocina principal atraer MDSC al tumor primario. Ensayo in vitro utilizando MDSC purificada demostr&oacute; que v&iacute;as de se&ntilde;alizaci&oacute;n de TGF-&beta;, EGF y HGF todos sirven a MDSC para inducir EMT en las c&eacute;lulas cancerosas. Estos resultados explican c&oacute;mo las c&eacute;lulas cancerosas adquieren un fenotipo m&oacute;vil tan temprano y proporcionan una explicaci&oacute;n mecanicista para el enlace largo reconocida entre la progresi&oacute;n de la inflamaci&oacute;n y c&aacute;ncer.

Transici&oacute;n mesenquimal y diseminaci&oacute;n de las c&eacute;lulas cancerosas es conducida por las c&eacute;lulas mieloides derivados supresor infiltr&aacute;ndose en el tumor primario.

Epithelial Mesenchymal Transition (EMT) is a crucial mechanism for carcinoma progression, as it provides routes for in situ carcinoma cells to dissociate and become motile, leading to localized invasion and metastatic spread. Targeting EMT therefore represents an important therapeutic strategy for cancer treatment. The discovery of oncogene addiction in sustaining tumor growth has led to the rapid development of targeted therapeutics. Whilst initially optimized as anti-proliferative agents, it is likely that some of these compounds may inhibit EMT initiation or sustenance, since EMT is also modulated by similar signaling pathways that these compounds were designed to target. We have developed a novel screening assay that can lead to the identification of compounds that can inhibit EMT initiated by growth factor signaling. This assay is designed as a high-content screening assay where both cell growth and cell migration can be analyzed simultaneously via time-course imaging in multi-well plates. Using this assay, we have validated several compounds as viable EMT inhibitors. In particular, we have identified compounds targeting ALK5, MEK, and SRC as potent inhibitors that can interfere with EGF, HGF, and IGF-1 induced EMT signaling. Overall, this EMT screening method provides a foundation for improving the therapeutic value of recently developed compounds in advanced stage carcinoma.

A cell-based small molecule screening method for identifying inhibitors of epithelial-mesenchymal transition in carcinoma.

Epithelial-mesenchymal transition (EMT) plays a critical role in the early stages of dissemination of carcinoma leading to metastatic tumors, which are responsible for over 90% of all cancer-related deaths. Current therapeutic regimens, however, have been ineffective in the cure of metastatic cancer, thus an urgent need exists to revisit existing protocols and to improve the efficacy of newly developed therapeutics. Strategies based on preventing EMT could potentially contribute to improving the outcome of advanced stage cancers. To achieve this goal new assays are needed to identify targeted drugs capable of interfering with EMT or to revert the mesenchymal-like phenotype of carcinoma to an epithelial-like state. Current assays are limited to examining the dispersion of carcinoma cells in isolation in conventional 2-dimensional (2D) microwell systems, an approach that fails to account for the 3-dimensional (3D) environment of the tumor or the essential interactions that occur with other nearby cell types in the tumor microenvironment. Here we present a microfluidic system that integrates tumor cell spheroids in a 3D hydrogel scaffold, in close co-culture with an endothelial monolayer. Drug candidates inhibiting receptor activation or signal transduction pathways implicated in EMT have been tested using dispersion of A549 lung adenocarcinoma cell spheroids as a metric of effectiveness. We demonstrate significant differences in response to drugs between 2D and 3D, and between monoculture and co-culture.

Screening therapeutic EMT blocking agents in a three-dimensional microenvironment.

Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.

MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma.

Oncogenesis in non-small cell lung cancer (NSCLC) is regulated by a complex signal transduction network. Single-agent targeted therapy fails frequently due to treatment insensitivity and acquired resistance. In this study, we demonstrate that co-inhibition of the MAPK and SRC pathways using a PD0325901 and Saracatinib kinase inhibitor combination can abrogate tumor growth in NSCLC. PD0325901/Saracatinib at 0.25:1 combination was screened against a panel of 28 NSCLC cell lines and 68% of cell lines were found to be sensitive (IC50 < 2 μM) to this combination. In Snail1 positive NSCLC lines, the drug combination complementarily enhanced mesenchymal-epithelial transition (MET), increasing both E-cadherin and Plakoglobin expression, and reducing Snail1, FAK and PXN expression. In addition, the drug combination abrogated cell migration and matrigel invasion. The co-inhibition of MAPK and SRC induced strong G1/G0 cell cycle arrest in the NSCLC lines, inhibited anchorage independent growth and delayed tumor growth in H460 and H358 mouse xenografts. These data provide rationale for further investigating the combination of MAPK and SRC pathway inhibitors in advanced stage NSCLC.

Combinatorial treatment using targeted MEK and SRC inhibitors synergistically abrogates tumor cell growth and induces mesenchymal-epithelial transition in non-small-cell lung carcinoma.

Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential.

Wen Jing Sim

Translational Immunology,
Institute of Molecular and Cell Biology,
Translational Immunology, Institute of Molecular and Cell Biology

Agency for Science, Technology and Research

Generation of Immature, Mature and Tolerogenic Dendritic Cells with Differing Metabolic Phenotypes

Wen Jing Sim

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Translational Immunology,Institute of Molecular and Cell Biology,Translational Immunology, Institute of Molecular and Cell Biology

Agency for Science, Technology and Research

Generation of Immature, Mature and Tolerogenic Dendritic Cells with Differing Metabolic Phenotypes

Translational Immunology,
Institute of Molecular and Cell Biology,
Translational Immunology, Institute of Molecular and Cell Biology