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000182900 0247_ $$2ISSN$$a0099-7013
000182900 0247_ $$2ISSN$$a0099-7374
000182900 0247_ $$2ISSN$$a1538-7445
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000182900 041__ $$aEnglish
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000182900 1001_ $$00000-0002-5761-632X$$aAlsina-Sanchis, Elisenda$$b0$$eFirst author
000182900 245__ $$aEndothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages.
000182900 260__ $$aPhiladelphia, Pa.$$bAACR$$c2022
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000182900 520__ $$aEpithelial ovarian cancer (EOC) is one of the most lethal gynecologic cancers worldwide. EOC cells educate tumor-associated macrophages (TAM) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (EC) to facilitate metastasis. However, further work is required to establish whether the endothelium also influences the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature; this was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, CXCL2 was identified as a novel Notch/RBPJ target gene that regulated the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. Together, these findings indicate that EOC cells induce the tumor endothelium to secrete CXCL2 to establish an immunosuppressive microenvironment.Endothelial Notch signaling favors immunosuppression by increasing CXCL2 secretion to stimulate CD44 expression in macrophages, facilitating their education by tumor cells.
000182900 536__ $$0G:(DE-HGF)POF4-311$$a311 - Zellbiologie und Tumorbiologie (POF4-311)$$cPOF4-311$$fPOF IV$$x0
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000182900 650_7 $$097C5T2UQ7J$$2NLM Chemicals$$aCholesterol
000182900 650_7 $$2NLM Chemicals$$aRBPJ protein, human
000182900 650_7 $$2NLM Chemicals$$aImmunoglobulin J Recombination Signal Sequence-Binding Protein
000182900 650_7 $$2NLM Chemicals$$aRbpj protein, mouse
000182900 650_2 $$2MeSH$$aHumans
000182900 650_2 $$2MeSH$$aFemale
000182900 650_2 $$2MeSH$$aMice
000182900 650_2 $$2MeSH$$aAnimals
000182900 650_2 $$2MeSH$$aTumor-Associated Macrophages
000182900 650_2 $$2MeSH$$aEndothelial Cells: pathology
000182900 650_2 $$2MeSH$$aCarcinoma, Ovarian Epithelial: genetics
000182900 650_2 $$2MeSH$$aOvarian Neoplasms: pathology
000182900 650_2 $$2MeSH$$aTumor Microenvironment
000182900 650_2 $$2MeSH$$aEndothelium: metabolism
000182900 650_2 $$2MeSH$$aCholesterol
000182900 650_2 $$2MeSH$$aImmunoglobulin J Recombination Signal Sequence-Binding Protein: genetics
000182900 7001_ $$0P:(DE-He78)3d2b0a3563ccf6bc6ee65cf2976efe5f$$aMülfarth, Ronja$$b1$$eFirst author
000182900 7001_ $$0P:(DE-He78)68d90eb013f51c689f9ebea83a920858$$aMoll, Iris$$b2
000182900 7001_ $$0P:(DE-He78)289be1a18d5b28404f113c40bbd76578$$aBöhn, Sarah Verena$$b3
000182900 7001_ $$0P:(DE-He78)b27922c32bcdf07ca4d5f13ecdcfd100$$aWiedmann, Lena$$b4
000182900 7001_ $$00000-0003-2323-817X$$aJordana-Urriza, Lorea$$b5
000182900 7001_ $$0P:(DE-He78)0b08760d6f32b6f049214b4231328692$$aZiegelbauer, Tara$$b6
000182900 7001_ $$0P:(DE-He78)dd8afdb992341efdf1a1ce54d15e65f3$$aZimmer, Eleni$$b7
000182900 7001_ $$0P:(DE-He78)df29352b13734f9202e3b900aeef7754$$aTaylor, Jacqueline$$b8
000182900 7001_ $$0P:(DE-He78)95d56cbcb8b1bb5783526d136049e3df$$aDe Angelis Rigotti, Francesca$$b9
000182900 7001_ $$0P:(DE-He78)2df93ebfdc67577592330aa9c4cfad56$$aStögbauer, Adrian$$b10
000182900 7001_ $$00000-0003-0384-325X$$aGiaimo, Benedetto Daniele$$b11
000182900 7001_ $$aCerwenka, Adelheid$$b12
000182900 7001_ $$00000-0003-4325-5452$$aBorggrefe, Tilman$$b13
000182900 7001_ $$0P:(DE-He78)039283a5d51058ec79156d0ef67132da$$aFischer, Andreas$$b14$$eLast author
000182900 7001_ $$00000-0001-9547-5508$$aRodriguez-Vita, Juan$$b15$$eLast author
000182900 773__ $$0PERI:(DE-600)2036785-5$$a10.1158/0008-5472.CAN-22-0076$$gVol. 82, no. 23, p. 4414 - 4428$$n23$$p4414 - 4428$$tCancer research$$v82$$x0008-5472$$y2022
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