TY  - JOUR
AU  - Alsina-Sanchis, Elisenda
AU  - Mülfarth, Ronja
AU  - Moll, Iris
AU  - Böhn, Sarah Verena
AU  - Wiedmann, Lena
AU  - Jordana-Urriza, Lorea
AU  - Ziegelbauer, Tara
AU  - Zimmer, Eleni
AU  - Taylor, Jacqueline
AU  - De Angelis Rigotti, Francesca
AU  - Stögbauer, Adrian
AU  - Giaimo, Benedetto Daniele
AU  - Cerwenka, Adelheid
AU  - Borggrefe, Tilman
AU  - Fischer, Andreas
AU  - Rodriguez-Vita, Juan
TI  - Endothelial RBPJ Is Essential for the Education of Tumor-Associated Macrophages.
JO  - Cancer research
VL  - 82
IS  - 23
SN  - 0008-5472
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2022-03003
SP  - 4414 - 4428
PY  - 2022
N1  - #EA:A270#LA:A270#
AB  - Epithelial 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.
KW  - Humans
KW  - Female
KW  - Mice
KW  - Animals
KW  - Tumor-Associated Macrophages
KW  - Endothelial Cells: pathology
KW  - Carcinoma, Ovarian Epithelial: genetics
KW  - Ovarian Neoplasms: pathology
KW  - Tumor Microenvironment
KW  - Endothelium: metabolism
KW  - Cholesterol
KW  - Immunoglobulin J Recombination Signal Sequence-Binding Protein: genetics
KW  - Cholesterol (NLM Chemicals)
KW  - RBPJ protein, human (NLM Chemicals)
KW  - Immunoglobulin J Recombination Signal Sequence-Binding Protein (NLM Chemicals)
KW  - Rbpj protein, mouse (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36200806
DO  - DOI:10.1158/0008-5472.CAN-22-0076
UR  - https://inrepo02.dkfz.de/record/182900
ER  -