Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer
Abstract Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 pat...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-03-01
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| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202103249 |
| _version_ | 1819157744607821824 |
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| author | Huayi Li Lorenzo Prever Myriam Y. Hsu Wen‐Ting Lo Jean Piero Margaria Maria Chiara De Santis Cristina Zanini Marco Forni Francesco Novelli Salvatore Pece Pier Paolo Di Fiore Paolo Ettore Porporato Miriam Martini Hassane Belabed Marc Nazare Volker Haucke Federico Gulluni Emilio Hirsch |
| author_facet | Huayi Li Lorenzo Prever Myriam Y. Hsu Wen‐Ting Lo Jean Piero Margaria Maria Chiara De Santis Cristina Zanini Marco Forni Francesco Novelli Salvatore Pece Pier Paolo Di Fiore Paolo Ettore Porporato Miriam Martini Hassane Belabed Marc Nazare Volker Haucke Federico Gulluni Emilio Hirsch |
| author_sort | Huayi Li |
| collection | DOAJ |
| description | Abstract Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy. |
| first_indexed | 2024-12-22T16:13:38Z |
| format | Article |
| id | doaj.art-ee0f506c019b414c91e9c0120c461dd3 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-12-22T16:13:38Z |
| publishDate | 2022-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-ee0f506c019b414c91e9c0120c461dd32022-12-21T18:20:25ZengWileyAdvanced Science2198-38442022-03-0199n/an/a10.1002/advs.202103249Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast CancerHuayi Li0Lorenzo Prever1Myriam Y. Hsu2Wen‐Ting Lo3Jean Piero Margaria4Maria Chiara De Santis5Cristina Zanini6Marco Forni7Francesco Novelli8Salvatore Pece9Pier Paolo Di Fiore10Paolo Ettore Porporato11Miriam Martini12Hassane Belabed13Marc Nazare14Volker Haucke15Federico Gulluni16Emilio Hirsch17Department of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyLeibniz‐Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin 13125 GermanyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyIEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan 20141 ItalyIEO European Institute of Oncology IRCCS Via Ripamonti 435 Milan 20141 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyLeibniz‐Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin 13125 GermanyLeibniz‐Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin 13125 GermanyLeibniz‐Forschungsinstitut für Molekulare Pharmakologie (FMP) Berlin 13125 GermanyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyDepartment of Molecular Biotechnology and Health Sciences University of Turin Turin 10126 ItalyAbstract Breast cancer is the most prevalent cancer and a major cause of death in women worldwide. Although early diagnosis and therapeutic intervention significantly improve patient survival rate, metastasis still accounts for most deaths. Here it is reported that, in a cohort of more than 2000 patients with breast cancer, overexpression of PI3KC2α occurs in 52% of cases and correlates with high tumor grade as well as increased probability of distant metastatic events, irrespective of the subtype. Mechanistically, it is demonstrated that PI3KC2α synthetizes a pool of PI(3,4)P2 at focal adhesions that lowers their stability and directs breast cancer cell migration, invasion, and metastasis. PI(3,4)P2 locally produced by PI3KC2α at focal adhesions recruits the Ras GTPase activating protein 3 (RASA3), which inactivates R‐RAS, leading to increased focal adhesion turnover, migration, and invasion both in vitro and in vivo. Proof‐of‐concept is eventually provided that inhibiting PI3KC2α or lowering RASA3 activity at focal adhesions significantly reduces the metastatic burden in PI3KC2α‐overexpressing breast cancer, thereby suggesting a novel strategy for anti‐breast cancer therapy.https://doi.org/10.1002/advs.202103249breast cancerfocal adhesionsmetastasesmigrationPI3KC2αRASA3 |
| spellingShingle | Huayi Li Lorenzo Prever Myriam Y. Hsu Wen‐Ting Lo Jean Piero Margaria Maria Chiara De Santis Cristina Zanini Marco Forni Francesco Novelli Salvatore Pece Pier Paolo Di Fiore Paolo Ettore Porporato Miriam Martini Hassane Belabed Marc Nazare Volker Haucke Federico Gulluni Emilio Hirsch Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer Advanced Science breast cancer focal adhesions metastases migration PI3KC2α RASA3 |
| title | Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer |
| title_full | Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer |
| title_fullStr | Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer |
| title_full_unstemmed | Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer |
| title_short | Phosphoinositide Conversion Inactivates R‐RAS and Drives Metastases in Breast Cancer |
| title_sort | phosphoinositide conversion inactivates r ras and drives metastases in breast cancer |
| topic | breast cancer focal adhesions metastases migration PI3KC2α RASA3 |
| url | https://doi.org/10.1002/advs.202103249 |
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