Ovarian tumor cell-derived JAGGED2 promotes omental metastasis through stimulating the Notch signaling pathway in the mesothelial cells

Syed S. Islam, Falah Almohanna, Iman M. Yousef, Ismail A. Al‐Badawi, Abdelilah Aboussekhra
In: Cell Death & Disease · 2024 · vol. 15(4) , pp. 247 · doi:10.1038/s41419-024-06512-0 · PMID:38575576 · W4393941479
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

Ovarian tumor-derived Jagged2 activates mesothelial Notch signaling to promote omental metastasis and tumor growth via IL-6 release, and this pathway is a potential therapeutic target.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study investigated how ovarian cancer cells contribute to omental metastasis by examining the role of the Notch ligand Jagged2 in activating Notch signaling in single-layered omental mesothelial cells, using patient-derived tissue comparisons, primary human omental cell co-culture systems, and mouse omental metastasis models. The authors report that tumor-cell–produced Jagged2 is a clinically and functionally critical mediator of omental metastasis, promoting tumor growth and therapeutic resistance via mesothelial IL-6 release and acting downstream of TGF-β released during omental destruction, with improved blockade when Notch signaling was disrupted directly in mesothelial cells (e.g., with MRK-003). A key caveat is that mechanistic evidence is largely generated in experimental co-culture/xenograft settings and involves a relatively small number of patient tissue samples (four metastatic and four non-metastatic omentum specimens). This paper is centrally about endometriosis and adenomyosis: it focuses on ovarian cancer–driven omental metastasis and does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

The primary site of metastasis for epithelial ovarian cancer (EOC) is the peritoneum, and it occurs through a multistep process that begins with adhesive contacts between cancer cells and mesothelial cells. Despite evidence that Notch signaling has a role in ovarian cancer, it is unclear how exactly it contributes to ovarian cancer omental metastasis, as well as the cellular dynamics and intrinsic pathways that drive this tropism. Here we show that tumor cells produced the Notch ligand Jagged2 is a clinically and functionally critical mediator of ovarian cancer omental metastasis by activating the Notch signaling in single-layered omental mesothelial cells. In turn, Jagged2 promotes tumor growth and therapeutic resistance by stimulating IL-6 release from mesothelial cells. Additionally, Jagged2 is a potent downstream mediator of the omental metastasis cytokine TGF-β that is released during omental destruction. Importantly, therapeutic inhibition of Jagged2-mediated omental metastasis was significantly improved by directly disrupting the Notch pathway in omental mesothelial cells. These findings highlight the key role of Jagged2 to the functional interplay between the TGF-β and the Notch signaling pathways during the metastatic process of ovarian cancer cells to the omentum and identify the Notch signaling molecule as a precision therapeutic target for ovarian cancer metastasis.

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