Open AccessNF‐κB ‐dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells
Author(s) -
Raynard Clotilde,
Ma Xingjie,
Huna Anda,
Tessier Nolwenn,
Massemin Amélie,
Zhu Kexin,
Flaman JeanMichel,
Moulin Florentin,
Goehrig Delphine,
Medard JeanJacques,
Vindrieux David,
Treilleux Isabelle,
HernandezVargas Hector,
Ducreux Sylvie,
Martin Nadine,
Bernard David
Publication year - 2022
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13632
Subject(s) - transdifferentiation , paracrine signalling , biology , senescence , cancer research , microbiology and biotechnology , immune system , phenotype , cancer , secretion , breast cancer , cancer cell , fibrosis , immunology , endocrinology , medicine , receptor , stem cell , genetics , gene , biochemistry
Cellular senescence is characterized by a stable proliferation arrest in response to stresses and the acquisition of a senescence‐associated secretory phenotype, called SASP, composed of numerous factors including pro‐inflammatory molecules, proteases, and growth factors. The SASP affects the environment of senescent cells, especially during aging, by inducing and modulating various phenotypes such as paracrine senescence, immune cell activity, and extracellular matrix deposition and organization, which critically impact various pathophysiological situations, including fibrosis and cancer. Here, we uncover a novel paracrine effect of the SASP: the neuroendocrine transdifferentiation (NED) of some epithelial cancer cells, evidenced both in the breast and prostate. Mechanistically, this effect is mediated by NF‐κB‐dependent SASP factors, and leads to an increase in intracellular Ca 2+ levels. Consistently, buffering Ca 2+ by overexpressing the CALB1 buffering protein partly reverts SASP‐induced NED, suggesting that the SASP promotes NED through a SASP‐induced Ca 2+ signaling. Human breast cancer dataset analyses support that NED occurs mainly in p53 WT tumors and in older patients, in line with a role of senescent cells and its secretome, as they are increasing during aging. In conclusion, our work, uncovering SASP‐induced NED in some cancer cells, paves the way for future studies aiming at better understanding the functional link between senescent cell accumulation during aging, NED and clinical patient outcome.