Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival

Abstract

In chemotherapy-treated breast cancer, wild-type p53 preferentially induces senescence over apoptosis, resulting in a persisting cell population constituting residual disease that drives relapse and poor patient survival via the senescence-associated secretory phenotype. Understanding the properties of tumor cells that allow survival after chemotherapy treatment is paramount. Using time-lapse and confocal microscopy to observe interactions of cells in treated tumors, we show here that chemotherapy-induced senescent cells frequently engulf both neighboring senescent or nonsenescent tumor cells at a remarkable frequency. Engulfed cells are processed through the lysosome and broken down, and cells that have engulfed others obtain a survival advantage. Gene expression analysis showed a marked up-regulation of conserved macrophage-like program of engulfment in chemotherapy-induced senescent cell lines and tumors. Our data suggest compelling explanations for how senescent cells persist in dormancy, how they manage the metabolically expensive process of cytokine production that drives relapse in those tumors that respond the worst, and a function for their expanded lysosomal compartment.

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

“…The cells that escaped senescence exhibited more invasive and migratory properties. In fact, it has recently been reported that doxorubicin-induced senescent breast tumor cells develop a cannibalistic capacity that allows for the engulfment of adjacent senescent and non-senescent neighbors [164]. This acquisition of a phagocytic capability enables senescent cells to hijack nutrient cargos from other cells, which can then be utilized to prolong their survival, providing an additional explanation for how senescent tumor cells can persist following exposure to anticancer therapy [165].…”

Senescent cells feed on their neighbours

“…However, these cells can promote tumour survival by secreting growth factors and signalling molecules called cytokines in a process termed the senescence-associated secretory phenotype (SASP) response 2 . Tonnessen-Murray et al 4 report studies of breast cancer in mice which reveal that this type of senescent cell takes up (engulfs) and digests neighbouring living cells. The cells are engulfed by a process that has molecular characteristics of phagocytosis, an engulfment process that immune cells use.…”

“…Ancient air trapped in Antarctic ice can be extracted from cores drilled from the ice sheet, allowing the CO 2 concentration to be measured directly, but the ice-core record extends to only 800,000 years ago 4 . Estimates of CO 2 concentrations from earlier periods have been made by measuring the ratio of boron isotopes in shells found in ancient marine sediments 5,6 .…”

“…Senescent cells typically never divide (although there are some rare examples of cells exiting senescence and resuming division), but they can persist in tissues and contribute to ageing and cancer progression 2,3 . Writing in the Journal of Cell Biology, Tonnessen-Murray et al 4 reveal a deadly activity that underlies the persistence of senescent cells -they can eat their neighbours alive.…”

Beware of thy neighbor: Senescent cancer cells feast on adjacent cells to persist

“…To dissect the molecular mechanisms underlying the observed phenotype, Tonnessen-Murray et al (8) performed an RNA-sequencing analysis in doxorubicin-treated cancer cells collected at two different time points: before (24 h) and after the CISC-related cell engulfment reaches its peak (8 d). Intriguingly, with respect to untreated cells, the gene set enrichment analysis unveiled the induction of several pathways, including cell cycle arrest, lysosomal signature, and phagocytosis, thus suggesting that cells surviving doxorubicin treatment activate a macrophage-like transcriptional program that allows CISCs to surround neighboring cells, engulf them, and digest them via the lysosomes.…”