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

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.

Automated summary

Osteosarcoma (OS) is a pediatric bone tumor with high heterogeneity. The discrepancy in tumorigenicity among OS cell lines is not fully understood. In this study, we investigated the potential role of mechanotransduction in OS tumorigenicity using in vitro and in vivo models. We found impaired mechanosensing and downregulation of rigidity-sensing proteins in transformed OS cells, as well as a novel TP53 mutation (R156P) that inhibits rigidity sensing. Our findings suggest that rigidity-sensing components play a fundamental role in OS tumorigenicity and mutant TP53 serves as an executor for malignant programs.