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EDI3 knockdown in ER-HER2+ breast cancer cells reduces tumor burden and improves survival in two mouse models of experimental metastasis

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Název: EDI3 knockdown in ER-HER2+ breast cancer cells reduces tumor burden and improves survival in two mouse models of experimental metastasis
Autoři: Glotzbach, Annika, Rohlf, Katharina, Gonscharow, Anastasia, Lüke, Simon, Demirci, Özlem, Begher-Tibbe, Brigitte, Overbeck, Nina, Reinders, Jörg, Cadenas, Cristina, Hengstler, Jan G., Edlund, Karolina, Marchan, Rosemarie
Zdroj: Breast Cancer Res
Breast Cancer Research, Vol 26, Iss 1, Pp 1-20 (2024)
Informace o vydavateli: Springer Science and Business Media LLC, 2024.
Rok vydání: 2024
Témata: Glycerophospholipid metabolism, 0301 basic medicine, Lung Neoplasms, Receptor, ErbB-2, Cell Line, Tumor [MeSH], Receptor, ErbB-2/metabolism [MeSH], Lung Neoplasms/genetics [MeSH], Metastasis, Breast cancer, Cell Movement [MeSH], Receptor, ErbB-2/genetics [MeSH], Tumor Burden [MeSH], Disease Models, Animal [MeSH], HER2 positive breast cancer, Breast Neoplasms/pathology [MeSH], Anoikis, Female [MeSH], Cell Proliferation [MeSH], Phospholipases/genetics [MeSH], Receptors, Estrogen/metabolism [MeSH], Humans [MeSH], Neoplasm Metastasis [MeSH], Breast Neoplasms/genetics [MeSH], Gene Knockdown Techniques [MeSH], Breast Neoplasms/metabolism [MeSH], Animals [MeSH], GPCPD1, Mice [MeSH], Phospholipases/metabolism [MeSH], Research, Lung Neoplasms/pathology [MeSH], Lung Neoplasms/metabolism [MeSH], Choline metabolism, Lung Neoplasms/secondary [MeSH], Breast Neoplasms, Mice, 03 medical and health sciences, Cell Movement, Cell Line, Tumor, Animals, Humans, Neoplasm Metastasis, RC254-282, Cell Proliferation, 0303 health sciences, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Tumor Burden, 3. Good health, Disease Models, Animal, Receptors, Estrogen, Phospholipases, Gene Knockdown Techniques, Female
Popis: Background Despite progress understanding the mechanisms underlying tumor spread, metastasis remains a clinical challenge. We identified the choline-producing glycerophosphodiesterase, EDI3 and reported its association with metastasis-free survival in endometrial cancer. We also observed that silencing EDI3 slowed cell migration and other cancer-relevant phenotypes in vitro. Recent work demonstrated high EDI3 expression in ER-HER2+ breast cancer compared to the other molecular subtypes. Silencing EDI3 in ER-HER2+ cells significantly reduced cell survival in vitro and decreased tumor growth in vivo. However, a role for EDI3 in tumor metastasis in this breast cancer subtype was not explored. Therefore, in the present work we investigate whether silencing EDI3 in ER-HER2+ breast cancer cell lines alters phenotypes linked to metastasis in vitro, and metastasis formation in vivo using mouse models of experimental metastasis. Methods To inducibly silence EDI3, luciferase-expressing HCC1954 cells were transduced with lentiviral particles containing shRNA oligos targeting EDI3 under the control of doxycycline. The effect on cell migration, adhesion, colony formation and anoikis was determined in vitro, and significant findings were confirmed in a second ER-HER2+ cell line, SUM190PT. Doxycycline-induced HCC1954-luc shEDI3 cells were injected into the tail vein or peritoneum of immunodeficient mice to generate lung and peritoneal metastases, respectively and monitored using non-invasive bioluminescence imaging. Metabolite levels in cells and tumor tissue were analyzed using targeted mass spectrometry and MALDI mass spectrometry imaging (MALDI-MSI), respectively. Results Inducibly silencing EDI3 reduced cell adhesion and colony formation, as well as increased susceptibility to anoikis in HCC1954-luc cells, which was confirmed in SUM190PT cells. No influence on cell migration was observed. Reduced luminescence was seen in lungs and peritoneum of mice injected with cells expressing less EDI3 after tail vein and intraperitoneal injection, respectively, indicative of reduced metastasis. Importantly, mice injected with EDI3-silenced cells survived longer. Closer analysis of the peritoneal organs revealed that silencing EDI3 had no effect on metastatic organotropism but instead reduced metastatic burden. Finally, metabolic analyses revealed significant changes in choline and glycerophospholipid metabolites in cells and in pancreatic metastases in vivo. Conclusions Reduced metastasis upon silencing supports EDI3’s potential as a treatment target in metastasizing ER-HER2+ breast cancer.
Druh dokumentu: Article
Other literature type
Jazyk: English
ISSN: 1465-542X
DOI: 10.1186/s13058-024-01849-y
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/38816770
https://doaj.org/article/f5f898d38fee442c8efa7d5ee8240227
https://repository.publisso.de/resource/frl:6524446
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Přístupové číslo: edsair.doi.dedup.....226799c0c35c18f552b46492efc125ec
Databáze: OpenAIRE
Popis
Abstrakt:Background Despite progress understanding the mechanisms underlying tumor spread, metastasis remains a clinical challenge. We identified the choline-producing glycerophosphodiesterase, EDI3 and reported its association with metastasis-free survival in endometrial cancer. We also observed that silencing EDI3 slowed cell migration and other cancer-relevant phenotypes in vitro. Recent work demonstrated high EDI3 expression in ER-HER2+ breast cancer compared to the other molecular subtypes. Silencing EDI3 in ER-HER2+ cells significantly reduced cell survival in vitro and decreased tumor growth in vivo. However, a role for EDI3 in tumor metastasis in this breast cancer subtype was not explored. Therefore, in the present work we investigate whether silencing EDI3 in ER-HER2+ breast cancer cell lines alters phenotypes linked to metastasis in vitro, and metastasis formation in vivo using mouse models of experimental metastasis. Methods To inducibly silence EDI3, luciferase-expressing HCC1954 cells were transduced with lentiviral particles containing shRNA oligos targeting EDI3 under the control of doxycycline. The effect on cell migration, adhesion, colony formation and anoikis was determined in vitro, and significant findings were confirmed in a second ER-HER2+ cell line, SUM190PT. Doxycycline-induced HCC1954-luc shEDI3 cells were injected into the tail vein or peritoneum of immunodeficient mice to generate lung and peritoneal metastases, respectively and monitored using non-invasive bioluminescence imaging. Metabolite levels in cells and tumor tissue were analyzed using targeted mass spectrometry and MALDI mass spectrometry imaging (MALDI-MSI), respectively. Results Inducibly silencing EDI3 reduced cell adhesion and colony formation, as well as increased susceptibility to anoikis in HCC1954-luc cells, which was confirmed in SUM190PT cells. No influence on cell migration was observed. Reduced luminescence was seen in lungs and peritoneum of mice injected with cells expressing less EDI3 after tail vein and intraperitoneal injection, respectively, indicative of reduced metastasis. Importantly, mice injected with EDI3-silenced cells survived longer. Closer analysis of the peritoneal organs revealed that silencing EDI3 had no effect on metastatic organotropism but instead reduced metastatic burden. Finally, metabolic analyses revealed significant changes in choline and glycerophospholipid metabolites in cells and in pancreatic metastases in vivo. Conclusions Reduced metastasis upon silencing supports EDI3’s potential as a treatment target in metastasizing ER-HER2+ breast cancer.
ISSN:1465542X
DOI:10.1186/s13058-024-01849-y