Mutant IDH1 Depletion Downregulates Integrins and Impairs Chondrosarcoma Growth.

Luyuan Li,Joanna Desalvo,Breelyn A Wilky,Jinbo Yue,Xiaoyu Hu,Josiane E Eid,Jonathan C Trent,Karina Galoian,Xiaodian Sun,Yuguang Ban,Marzenna Blonska,Xi Steven Chen,Andrew E Rosenberg

doi:10.3390/cancers12010141

Abstract

Chondrosarcomas are a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers, including conventional and dedifferentiated chondrosarcomas. These mutations lead to the inability of IDH to convert isocitrate into α-ketoglutarate (α-KG). Instead, α-KG is reduced into D-2-hydroxyglutarate (D-2HG), an oncometabolite. IDH mutations and D-2HG are thought to contribute to tumorigenesis due to the role of D-2HG as a competitive inhibitor of α-KG-dependent dioxygenases. However, the function of IDH mutations in chondrosarcomas has not been clearly defined. In this study, we knocked out mutant IDH1 (IDH1mut) in two chondrosarcoma cell lines using the CRISPR/Cas9 system. We observed that D-2HG production, anchorage-independent growth, and cell migration were significantly suppressed in the IDH1mut knockout cells. Loss of IDH1mut also led to a marked attenuation of chondrosarcoma formation and D-2HG production in a xenograft model. In addition, RNA-Seq analysis of IDH1mut knockout cells revealed downregulation of several integrin genes, including those of integrin alpha 5 (ITGA5) and integrin beta 5 (ITGB5). We further demonstrated that deregulation of integrin-mediated processes contributed to the tumorigenicity of IDH1-mutant chondrosarcoma cells. Our findings showed that IDH1mut knockout abrogates chondrosarcoma genesis through modulation of integrins. This suggests that integrin molecules are appealing candidates for combinatorial regimens with IDH1mut inhibitors for chondrosarcomas that harbor this mutation.

Highlights

Chondrosarcoma constitutes a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix
We found that loss of IDH1mut attenuated the tumorigenicity of chondrosarcoma cells and led to a marked attenuation of chondrosarcoma formation and D-2HG production
We have previously reported that pharmacological inhibition of IDH1mut in human chondrosarcoma cells led to decreased production of D-2HG and suppressed their tumorigenic properties [9]

Summary

Introduction

Chondrosarcoma constitutes a heterogeneous group of malignant bone tumors that produce hyaline cartilaginous matrix. It is the second most common primary malignancy of bone following osteosarcoma. Chondrosarcomas that arise de novo are called primary chondrosarcomas while those superimposed on preexisting benign cartilaginous neoplasms such as enchondroma or osteochondroma are referred to as secondary chondrosarcomas [1]. 85% of all chondrosarcomas are the conventional subtypes further classified into central, peripheral and periosteal lesions according to the osseous location. The remaining 10–15% consist of rare subtypes including dedifferentiated, mesenchymal, and clear cell chondrosarcoma. Conventional chondrosarcoma most often arises in individuals over 40 years of age, and may be associated with significant morbidity and mortality [2,3]

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