Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis

Abstract

Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context.

Keywords: cellular plasticity; epithelial-mesenchymal transition; immune evasion; reprogramming; senescence.

Figure 1

Dualistic model for tumor initiation. Stem cells are quiescent and present intrinsic EMT-dependent plasticity features. Stem cells are able to bypass senescence and give rise to genomically stable tumors [95]. Inversely, the escape from senescence of differentiated cells requires the acquisition of polyploidy and extensive cellular reprogramming, resulting in genomically rearranged tumors. Stasis: stress-associated senescence barrier. RS: replicative senescence. OIS: oncogene-induced senescence. This figure was made using elements from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com (accessed on 17 August 2021).

Figure 2

Immune evasion of senescent cells through acquisition of plasticity. (A) The acquisition of plasticity during senescence escape alters the secretory phenotype, leading to a redirection of macrophage polarization, preventing the clearance of senescent cancer cells [124]. EMT/plasticity modulates the expression of immune receptors (downregulated MHC-I) and the recognition of senescent cells by the immune system. (B) The SASP produced by senescent cancer cells leads to the recruitment of immature monocytes (MDSCs). Their maturation is prevented by adjacent cancer cells through metabolic modification of the tumor microenvironment (TME) [142]. The accumulation of MDSCs unable to polarize into M1, nor recruit NKs [143] or CD8+ T cells, in turn leads to the creation of an immune umbrella for cancer cell growth and will promote metastatic progression via the enhancement of EMT. This figure was made using elements from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com (accessed on 17 August 2021).

Figure 3

Plasticity acquired following senescence escape leads to the modulation of innate immunity. Senescence induced by different stimuli activates the production of an inflammatory secretory phenotype (SASP) under the control of the cGAS/STING/NFKB pathway. Its activation is required for the recruitment of immune cells and the clearance of senescent cancer cells by the innate immune system. On the other hand, SASP, together with polyploidy and EMT features acquired after escape from senescence, leads to the enhanced cancer cell plasticity associated with a deleterious secretory phenotype, allowing immune evasion of cancer cells. This figure was made using elements from Servier Medical Art, which are licensed under a Creative Commons Attribution 3.0 Unported License: https://smart.servier.com (accessed on 17 August 2021).