CD73 contributes to the pathogenesis of fusion- negative rhabdomyosarcoma through the purinergic signaling pathway

• 成果类型: Article
• 署名作者: Hernandez, Karla Cano; Shah, Akansha M.; Lopez, Victor A.; Tagliabracci, Vincent S.; Chen, Kenian; Xu, Lin; Bassel-Duby, Rhonda; Olson, Eric N.; Liu, Ning
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Howard Hughes Medical Institute; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14233
• DOI: 10.1073/pnas.2315925121
• 发表日期: 2024-01-23
• 关键词: targeting cd73; adenosine

摘要

Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children and adolescents. Fusion- negative RMS (FN- RMS) accounts for more than 80% of all RMS cases. The long- term event- free survival rate for patients with high- grade FN- RMS is below 30%, highlighting the need for improved therapeutic strategies. CD73 is a 5 ' ectonucleotidase that hydrolyzes AMP to adenosine and regulates the purinergic signaling pathway. We found that CD73 is elevated in FN- RMS tumors that express high levels of TWIST2. While high expression of CD73 contributes to the pathogenesis of multiple cancers, its role in FN- RMS has not been investigated. We found that CD73 knockdown decreased FN- RMS cell growth while up- regulating the myogenic differentiation program. Moreover, mutation of the catalytic residues of CD73 rendered the protein enzymatically inactive and abolished its ability to stimulate FN- RMS growth. Overexpression of wildtype CD73, but not the catalytically inactive mutant, in CD73 knockdown FN- RMS cells restored their growth capacity. Likewise, treatment with an adenosine receptor A2A- B agonist partially rescued FN- RMS cell proliferation and bypassed the CD73 knockdown defective growth phenotype. These results demonstrate that the catalytic activity of CD73 contributes to the pathogenic growth of FN- RMS through the activation of the purinergic signaling pathway. Therefore, targeting CD73 and the purinergic signaling pathway represents a potential therapeutic approach for FN- RMS patients.