NF‐κB‐dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells. Issue 7 (2nd June 2022)

• Record Type: Journal Article
• Authors: Raynard, Clotilde; Ma, Xingjie; Huna, Anda; Tessier, Nolwenn; Massemin, Amélie; Zhu, Kexin; Flaman, Jean‐Michel; Moulin, Florentin; Goehrig, Delphine; Medard, Jean‐Jacques; Vindrieux, David; Treilleux, Isabelle; Hernandez‐Vargas, Hector; Ducreux, Sylvie; Martin, Nadine; Bernard, David
• Is Part Of: Aging cell. Volume 21:Issue 7(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-06-02
• Subjects: aging -- breast cancer -- cellular senescence -- neuroendocrine transdifferentiation -- senescence‐associated secretory phenotype; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.13632
• Languages: English
• ISSNs: 1474-9718

Abstract

Abstract: 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. Abstract : Senescent cells, which can accumulate during aging or after stresses, secrete many factors. The pro‐inflammatory NF‐kappaB‐dependent secretome induces neuroendocrine transdifferentiation of breast cancer epithelial cells.