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Original Article | Open Access

Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma

Ming Luo1,, Mingyang Huang1,, Ningning Yang2,3, Yufan Zhu1, Peng Huang1, Zhujun Xu1, Wengang Wang2 ( ), Lin Cai1( )
Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

These authors contributed equally: Ming Luo, Mingyang Huang

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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.

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Bone Research
Volume 11,
December 2023
Article number: 28
DOI: 10.1038/s41413-023-00265-w
Cite this article:
Luo M, Huang M, Yang N, et al. Impairment of rigidity sensing caused by mutant TP53 gain of function in osteosarcoma. Bone Research, 2023, 11: 28. https://doi.org/10.1038/s41413-023-00265-w

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Received: 04 December 2022
Revised: 23 February 2023
Accepted: 18 April 2023
Published: 29 May 2023
© The Author(s) 2023

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