A system-level approach identifies HIF-2\u03b1 as a critical regulator of chondrosarcoma progression

Hyeonkyeong Kim,Jin-Hong Kim,Moon Jong Chang,Donghyeon Cheon,Chong Bum Chang,Hyun Guy Kang,Yongsik Cho,Kyoung Min Lee,Seung-Baik Kang,Donghyun Kang,Hyeon-Seop Kim,Yi-Jun Kim

doi:10.1038/s41467-020-18817-7

Abstract

Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma.

Highlights

Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality
We focused on the remaining three moderately sized modules (M1: 263 genes, M2: 265 genes, and M3: 418 genes) that activation of which may be governed by a single transcriptional unit in human chondrosarcoma (Fig. 1a and Supplementary Table 1)
We identified a specific association between HIF-2α expression and several aspects of chondrosarcoma malignancy, there has been a general notion of redundancy between HIF-1α and HIF-2α as a common downstream effector of hypoxia

Summary

Introduction

Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. The vast majority (>85%) of chondrosarcomas are central chondrosarcomas that arise from an intramedullary location[3], surrounded by thick layers of bone matrix and rarely exhibiting metastatic cell survival and outgrowth[1,2]. These types of low-grade chondrosarcomas remain dormant without noticeable symptoms. The heterogeneity of the chondrosarcoma genome presents a major obstacle for the development of effective therapeutic strategies for this disease[4,21]

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