Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma
Abstract Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, t...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-05-01
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| Series: | Bone Research |
| Online Access: | https://doi.org/10.1038/s41413-023-00265-w |
| _version_ | 1797811605221670912 |
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| author | Ming Luo Mingyang Huang Ningning Yang Yufan Zhu Peng Huang Zhujun Xu Wengang Wang Lin Cai |
| author_facet | Ming Luo Mingyang Huang Ningning Yang Yufan Zhu Peng Huang Zhujun Xu Wengang Wang Lin Cai |
| author_sort | Ming Luo |
| collection | DOAJ |
| description | Abstract Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs. |
| first_indexed | 2024-03-13T07:25:11Z |
| format | Article |
| id | doaj.art-3d9058af01b246278d815bbf0468c809 |
| institution | Directory Open Access Journal |
| issn | 2095-6231 |
| language | English |
| last_indexed | 2024-03-13T07:25:11Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Bone Research |
| spelling | doaj.art-3d9058af01b246278d815bbf0468c8092023-06-04T11:23:27ZengNature Publishing GroupBone Research2095-62312023-05-0111111110.1038/s41413-023-00265-wImpairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcomaMing Luo0Mingyang Huang1Ningning Yang2Yufan Zhu3Peng Huang4Zhujun Xu5Wengang Wang6Lin Cai7Department of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Orthopedics, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Orthopedics, Zhongnan Hospital of Wuhan UniversityDepartment of Orthopedics, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Orthopedics, Zhongnan Hospital of Wuhan UniversityAbstract Osteosarcoma (OS) is the most common primary malignant pediatric bone tumor and is characterized by high heterogeneity. Studies have revealed a wide range of phenotypic differences among OS cell lines in terms of their in vivo tumorigenicity and in vitro colony-forming abilities. However, the underlying molecular mechanism of these discrepancies remains unclear. The potential role of mechanotransduction in tumorigenicity is of particular interest. To this end, we tested the tumorigenicity and anoikis resistance of OS cell lines both in vitro and in vivo. We utilized a sphere culture model, a soft agar assay, and soft and rigid hydrogel surface culture models to investigate the function of rigidity sensing in the tumorigenicity of OS cells. Additionally, we quantified the expression of sensor proteins, including four kinases and seven cytoskeletal proteins, in OS cell lines. The upstream core transcription factors of rigidity-sensing proteins were further investigated. We detected anoikis resistance in transformed OS cells. The mechanosensing function of transformed OS cells was also impaired, with general downregulation of rigidity-sensing components. We identified toggling between normal and transformed growth based on the expression pattern of rigidity-sensing proteins in OS cells. We further uncovered a novel TP53 mutation (R156P) in transformed OS cells, which acquired gain of function to inhibit rigidity sensing, thus sustaining transformed growth. Our findings suggest a fundamental role of rigidity-sensing components in OS tumorigenicity as mechanotransduction elements through which cells can sense their physical microenvironment. In addition, the gain of function of mutant TP53 appears to serve as an executor for such malignant programs.https://doi.org/10.1038/s41413-023-00265-w |
| spellingShingle | Ming Luo Mingyang Huang Ningning Yang Yufan Zhu Peng Huang Zhujun Xu Wengang Wang Lin Cai Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma Bone Research |
| title | Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma |
| title_full | Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma |
| title_fullStr | Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma |
| title_full_unstemmed | Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma |
| title_short | Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma |
| title_sort | impairment of rigidity sensing caused by mutant tp53 gain of function in osteosarcoma |
| url | https://doi.org/10.1038/s41413-023-00265-w |
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