Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis
Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell–lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Usin...
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-03-01
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| Series: | JCI Insight |
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| Online Access: | https://doi.org/10.1172/jci.insight.163019 |
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| author | Preety Bajwa Kasjusz Kordylewicz Agnes Bilecz Ricardo R. Lastra Kristen Wroblewski Yuval Rinkevich Ernst Lengyel Hilary A. Kenny |
| author_facet | Preety Bajwa Kasjusz Kordylewicz Agnes Bilecz Ricardo R. Lastra Kristen Wroblewski Yuval Rinkevich Ernst Lengyel Hilary A. Kenny |
| author_sort | Preety Bajwa |
| collection | DOAJ |
| description | Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell–lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin-mediated ablation in Msln-Cre mice significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietin-like 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell–induced monocyte migration, endothelial cell vessel formation, and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell–induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with Abs reduced the ex vivo colonization of 3 different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8p53–/–Brca2–/– cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis and that the crosstalk between mesothelial cells and the tumor microenvironment promotes OvCa metastasis through the secretion of ANGPTL4. |
| first_indexed | 2024-03-11T12:06:16Z |
| format | Article |
| id | doaj.art-076659f4596749819d856dc0aae51c1f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:16Z |
| publishDate | 2023-03-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-076659f4596749819d856dc0aae51c1f2023-11-07T16:25:22ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-03-0186Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasisPreety BajwaKasjusz KordylewiczAgnes BileczRicardo R. LastraKristen WroblewskiYuval RinkevichErnst LengyelHilary A. KennyOvarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell–lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin-mediated ablation in Msln-Cre mice significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietin-like 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell–induced monocyte migration, endothelial cell vessel formation, and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell–induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with Abs reduced the ex vivo colonization of 3 different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8p53–/–Brca2–/– cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis and that the crosstalk between mesothelial cells and the tumor microenvironment promotes OvCa metastasis through the secretion of ANGPTL4.https://doi.org/10.1172/jci.insight.163019Cell biologyOncology |
| spellingShingle | Preety Bajwa Kasjusz Kordylewicz Agnes Bilecz Ricardo R. Lastra Kristen Wroblewski Yuval Rinkevich Ernst Lengyel Hilary A. Kenny Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis JCI Insight Cell biology Oncology |
| title | Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis |
| title_full | Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis |
| title_fullStr | Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis |
| title_full_unstemmed | Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis |
| title_short | Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis |
| title_sort | cancer associated mesothelial cell derived angptl4 and stc1 promote the early steps of ovarian cancer metastasis |
| topic | Cell biology Oncology |
| url | https://doi.org/10.1172/jci.insight.163019 |
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