PT  - JOURNAL ARTICLE
AU  - Ronja Mülfarth
AU  - Elisenda Alsina-Sanchis
AU  - Iris Moll
AU  - Sarah Böhn
AU  - Lena Wiedmann
AU  - Lorea Jordana
AU  - Tara Ziegelbauer
AU  - Jacqueline Taylor
AU  - Francesca De Angelis Rigotti
AU  - Adrian Stögbauer
AU  - Benedetto Daniele Giaimo
AU  - Adelheid Cerwenka
AU  - Tilman Borggrefe
AU  - Andreas Fischer
AU  - Juan Rodriguez-Vita
TI  - Endothelial Rbpj is essential for the education of tumour-associated macrophages
AID  - 10.1101/2021.12.20.473423
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.12.20.473423
4099  - http://biorxiv.org/content/early/2022/05/23/2021.12.20.473423.short
4100  - http://biorxiv.org/content/early/2022/05/23/2021.12.20.473423.full
AB  - Epithelial ovarian cancer (EOC) is one of the most lethal gynaecological cancers worldwide. EOC cells educate tumour-associated macrophages (TAMs) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumour microenvironment (TME). In addition, tumour cells frequently activate Notch1 receptors on endothelial cells (ECs) to facilitate metastasis. However, little is known whether the endothelium would also influence the education of recruited monocytes. Here, we report that canonical Notch signalling 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 tumour burden. Mechanistically, we identified CXCL2 as a novel Notch/RBPJ target gene. This angiocrine factor regulates 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. As such, EOC cells employ the tumour endothelium to secrete CXCL2 in order to facilitate an immunosuppressive microenvironment.Competing Interest StatementThe authors have declared no competing interest.