Department of Physiology and Biophysics, Georgetown University, Washington, DC, United States.
New York Genome Center, New York, NY, United States.
Nat Commun. 2022 Apr 28;13(1):2323. doi: 10.1038/s41467-022-29898-x.
Adverse prognosis in Ewing sarcoma (ES) is associated with the presence of metastases, particularly in bone, tumor hypoxia and chromosomal instability (CIN). Yet, a mechanistic link between these factors remains unknown. We demonstrate that in ES, tumor hypoxia selectively exacerbates bone metastasis. This process is triggered by hypoxia-induced stimulation of the neuropeptide Y (NPY)/Y5 receptor (Y5R) pathway, which leads to RhoA over-activation and cytokinesis failure. These mitotic defects result in the formation of polyploid ES cells, the progeny of which exhibit high CIN, an ability to invade and colonize bone, and a resistance to chemotherapy. Blocking Y5R in hypoxic ES tumors prevents polyploidization and bone metastasis. Our findings provide evidence for the role of the hypoxia-inducible NPY/Y5R/RhoA axis in promoting genomic changes and subsequent osseous dissemination in ES, and suggest that targeting this pathway may prevent CIN and disease progression in ES and other cancers rich in NPY and Y5R.
尤文肉瘤（ES）的不良预后与转移的存在有关，特别是在骨骼中，肿瘤缺氧和染色体不稳定性（CIN）。然而，这些因素之间的机制联系仍然未知。我们证明，在 ES 中，肿瘤缺氧选择性地加剧了骨转移。这个过程是由缺氧诱导的神经肽 Y（NPY）/Y5 受体（Y5R）途径的刺激引发的，导致 RhoA 过度激活和胞质分裂失败。这些有丝分裂缺陷导致多倍体 ES 细胞的形成，其后代表现出高 CIN、侵袭和定植骨骼的能力以及对化疗的耐药性。在缺氧 ES 肿瘤中阻断 Y5R 可防止多倍体形成和骨转移。我们的研究结果为缺氧诱导的 NPY/Y5R/RhoA 轴在促进 ES 中的基因组改变和随后的骨播散中的作用提供了证据，并表明靶向该途径可能预防 ES 和其他富含 NPY 和 Y5R 的癌症中的 CIN 和疾病进展。
