Hepatocyte growth factor derived from senescent cells attenuates cell competition-induced apical elimination of oncogenic cells
Nanase Igarashi, Kenichi Miyata, Tze Mun Loo, Masatomo Chiba, Aki Hanyu, Mika Nishio, Hiroko Kawasaki, Hao Zheng, Shinya Toyokuni, Shunsuke Kon, Keiji Moriyama, Yasuyuki Fujita, Akiko Takahashi
Abstract
Cellular senescence and cell competition are important tumor suppression mechanisms that restrain cells with oncogenic mutations at the initial stage of cancer development. However, the link between cellular senescence and cell competition remains unclear. Senescent cells accumulated during the in vivo aging process contribute toward age-related cancers via the development of senescence-associated secretory phenotype (SASP). Here, we report that hepatocyte growth factor (HGF), a SASP factor, inhibits apical extrusion and promotes basal protrusion of Ras-mutated cells in the cell competition assay. Additionally, cellular senescence induced by a high-fat diet promotes the survival of cells with oncogenic mutations, whereas crizotinib, an inhibitor of HGF signaling, provokes the removal of mutated cells from mouse livers and intestines. Our study provides evidence that cellular senescence inhibits cell competition-mediated elimination of oncogenic cells through HGF signaling, suggesting that it may lead to cancer incidence during aging.