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

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.

Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype

“…Finally, recent findings from in vitro and in vivo models have reported a significant hypoxic microenvironment involvement via hypoxia-inducible factors (HIFs) in ChS development and progression, including the maintenance of stem-like phenotypes. HIF proteins were found overexpressed in ChS and correlated with the histological grade of the tumor, playing a pivotal role in the promotion of tumor growth, proliferation, metastasis, and the self-renewal potential of stem cells [ 59 , 60 , 61 ]. Moreover, some members of the HIF protein family can potentially be targeted by a pharmacological approach, and their inhibition was shown to overcome the chemoresistance of ChS and augment standard chemotherapeutics [ 59 ].…”

Metabolic Pathways and Targets in Chondrosarcoma

“…HIF-1α expression is highly expressed in the majority of chondrsarcomas and is associated with poor outcomes ( 14 ). Also, HIF-2α is upregulated in human high-grade chondrosarcoma biopsies compared to low grade samples and gene amplification is associated with poor prognosis in chondrosarcoma patients ( 15 ). HIF-2α promotes chondrosarcoma tumor growth, invasion and metastasis using xenograft models in vivo and pharmacological inhibition of HIF-2α induces apoptosis ( 15 ).…”

“…Also, HIF-2α is upregulated in human high-grade chondrosarcoma biopsies compared to low grade samples and gene amplification is associated with poor prognosis in chondrosarcoma patients ( 15 ). HIF-2α promotes chondrosarcoma tumor growth, invasion and metastasis using xenograft models in vivo and pharmacological inhibition of HIF-2α induces apoptosis ( 15 ). HIF-1α and HIF-2α are degraded in the proteosome via von-Hippel Lindau (VHL) and VHL disease is due to inactivating mutations in the VHL gene (pVHL), which leads to HIF-1α and HIF-2α stabilization ( 16 ).…”

Prognostic Factors in Conventional Chondrosarcoma Patients: a SEER Database Analysis

“…Chondrosarcoma is resistant to chemotherapy and radiotherapy because of its extracellular matrix, low percentage of dividing cells, and poor vascularity [1,7] . The identi cation of IDH1/2 [8] , COL2A1 [9] , and HIF2α [10] in chondrosarcoma may be related to targeted agents, although the future role and effectiveness of which are dismal. Surgical excision remains the mainstay of treatment.…”