Congyi Lu, Akanksha Mahajan, Sung-Hyeok Hong, Susana Galli, Shiya Zhu, Jason U Tilan, Nouran Abualsaud, Mina Adnani, Stacey Chung, Nada Elmansy, Jasmine Rodgers, Olga Rodriguez, Christopher Albanese, Hongkun Wang, Maureen Regan, Valerie Zgonc, Jan Blancato, Ewa Krawczyk, G Ian Gallicano, Michael Girgis, Amrita Cheema, Ewa Iżycka-Świeszewska, Luciane R Cavalli, Svetlana D Pack, Joanna Kitlinska
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...
April 28, 2022: Nature Communications