Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla

Abstract

Dormancy is a key survival strategy in many organisms across the tree of life. Organisms that utilize some type of dormancy (hibernation, aestivation, brumation, diapause, and quiescence) are able to survive in habitats that would otherwise be uninhabitable. Induction into dormant states is typically caused by environmental stress. While organisms are dormant, their physical activity is minimal, and their metabolic rates are severely depressed (hypometabolism). These metabolic reductions allow for the conservation and distribution of energy while conditions in the environment are poor. When conditions are more favorable, the organisms are then able to come out of dormancy and reengage in their environment. Polyaneuploid cancer cells (PACCs), proposed mediators of cancer metastasis and resistance, access evolutionary programs and employ dormancy as a survival mechanism in response to stress. Quiescence, the type of dormancy observed in PACCs, allows these cells the ability to survive stressful conditions (e.g., hypoxia in the microenvironment, transiting the bloodstream during metastasis, and exposure to chemotherapy) by downregulating and altering metabolic function, but then increasing metabolic activities again once stress has passed. We can gain insights regarding the mechanisms underlying PACC dormancy by looking to the evolution of dormancy in different organisms.

Lipid droplet evolution gives insight into polyaneuploid cancer cell lipid droplet functions

“…Cancer cells have been shown to accumulate LDs which drive tumor aggressiveness and chemotherapy resistance. Additionally, we and others have shown that the transient PACC state has greater accumulation of LDs than the typical cancer cell [30,54]. As PACCs are hypothesized to be lethal mediators of cancer metastasis and therapy resistance, understanding LD function in PACCs is crucial.…”

“…Cells in the PACC state contain a higher number of LDs than the cancer cells they are derived from (Fig. 1) [30,54]. As PACCs are hypothesized to be mediators of tumorigenesis, metastasis, and resistance, understanding their LD biology may be crucial in learning how to target them [18].…”

Therapy-Induced Senescent/Polyploid Cancer Cells Undergo Atypical Divisions Associated with Altered Expression of Meiosis, Spermatogenesis and EMT Genes

“…An increase in LDs can affect major cancer features, including cell growth, proliferation, metabolism, migration, inflammation, immunity, aggressiveness and chemotherapy resistance [ 57 ]. Interestingly, polyploid cancer cells have greater accumulation of LDs than nonpolyploid cancer cells [ 57 , 58 ]. In this study, we visualized the accumulation of LDs in senescent/polyploid cancer cells and showed the increased expression of genes involved in responses to lipids (D3).…”

A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells

“…PACCs are formed when aneuploid cancer cells bypass mitosis, cytokinesis, or both and undergo whole genome doubling via cell fusion, endocycling, or mitotic slippage. This cell state is characterized by (1) an exit of the cell cycle after S phase to pause cell division 21 , allowing PACCs to endure stressful environments by avoiding DNA damage and programmed cell death, and (2) an increase in genomic content through polyploidization, promoting a greater generation of heritable variation that can be dispensed to their aneuploid 2N+ progeny upon depolyploidization via neosis or multipolar cell division 22 – 25 . This leads to the rapid generation of heritably resistant cells.…”