Irinotecan treatment and senescence failure promote the emergence of more transformed and invasive cells that depend on anti-apoptotic Mcl-1

Abstract

Induction of senescence by chemotherapy was initially characterized as a suppressive response that prevents tumor cell proliferation. However, in response to treatment, it is not really known how cells can survive senescence and how irreversible this pathway is. In this study, we analyzed cell escape in response to irinotecan, a first line treatment used in colorectal cancer that induced senescence. We detected subpopulations of cells that adapted to chemotherapy and resumed proliferation. Survival led to the emergence of more transformed cells that induced tumor formation in mice and grew in low adhesion conditions. A significant amount of viable polyploid cells was also generated following irinotecan failure. Markers such as lgr5, CD44, CD133 and ALDH were downregulated in persistent clones, indicating that survival was not associated with an increase in cancer initiating cells. Importantly, malignant cells which resisted senescence relied on survival pathways induced by Mcl-1 signaling and to a lesser extent by Bcl-xL. Depletion of Mcl-1 increased irinotecan efficiency, induced the death of polyploid cells, prevented cell emergence and inhibited growth in low-adhesion conditions. We therefore propose that Mcl-1 targeting should be considered in the future to reduce senescence escape and to improve the treatment of irinotecan-refractory colorectal cancers.

Sénescence et cancer

“…Malheureusement, la sénescence induite par les thérapies anticancéreuses est peu stable. En effet, des cellules cancéreuses traitées à la doxorubicine ou à l'irinotecan, par exemple, entrent en sénescence mais, au cours du temps, certaines d'entre elles échappent à cet état [35][36][37][38].…”

tRNA Biogenesis and Specific Aminoacyl-tRNA Synthetases Regulate Senescence Stability Under the Control of mTOR

“…We and others have shown that this suppression functions as an adaptive mechanism in response to chemotherapy-induced -senescence (CIS) (7,9). We have described that cancer cells can escape senescence and emerge as more transformed cells that resist anoikis and are more invasive (14)(15)(16)(17). In addition, we have also shown that cells having an incomplete senescence response are characterized by a reduced expression of CD47 (17).…”

Proteomics Approaches to Define Senescence Heterogeneity and Chemotherapy Response

“…These deleterious effects are not limited to carcinogenesis. We and others have also shown that these arrested cells and the proteins they secrete play a key role in chemotherapy resistance, allowing the generation of more aggressive cells in response to genotoxic treatments . For instance, important results indicate that Wnt activation induces the dedifferentiation of senescent cells, the reactivation of cell cycle progression, and the generation of subpopulations with higher tumor initiation potential .…”

“…In this condition, we and others have shown that senescence relies on p21waf1 and it is not obvious that this protein is always acting as an inhibitor of cancer progression. Using different experimental models, we have shown that cancer cells enter senescence in response to chemotherapy but that persistent cells are able to escape this suppressive arrest . Senescence escape leads to the emergence of more transformed clones with enhanced potential for migration.…”