Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells

Abstract

We present a unifying theory to explain cancer recurrence, therapeutic resistance, and lethality. The basis of this theory is the formation of simultaneously polyploid and aneuploid cancer cells, polyaneuploid cancer cells (PACCs), that avoid the toxic effects of systemic therapy by entering a state of cell cycle arrest. The theory is independent of which of the classically associated oncogenic mutations have already occurred. PACCs have been generally disregarded as senescent or dying cells. Our theory states that therapeutic resistance is driven by PACC formation that is enabled by accessing a polyploid program that allows an aneuploid cancer cell to double its genomic content, followed by entry into a nondividing cell state to protect DNA integrity and ensure cell survival. Upon removal of stress, e.g., chemotherapy, PACCs undergo depolyploidization and generate resistant progeny that make up the bulk of cancer cells within a tumor.

Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla

“…Under stress PACCs are the majority of the population and enter into a quiescent state to survive. In this quiescent state PACCs contain high levels of lipids (Sirois et al, 2019), they do not reproduce (Pienta et al, 2021), and they are physically enlarged, similar to the enlarged S. cerevisiae. When stress is released, PACCs are able to undergo division (i.e., restart reproductive efforts) in the form of neosis (cell budding) to produce new, smaller progeny that are the same size as the original cell population (Figure 2C) (Sundaram et al, 2004;Zhang et al, 2013;Amend et al, 2019).…”

“…These cells, defined as PACCs, exhibit temporary polyploidization of their aneuploid genome while simultaneously altering their metabolism to survive environmental stress (Pienta et al, 2020a,c). Following polyploidization, PACCs halt cell proliferation, entering a dormant state (Pienta et al, 2021). Eventually, when stress is removed, PACCs exit the dormant state and generate progeny to establish a recurrence (Puig, 2008;Zhang et al, 2013;Amend et al, 2019).…”

“…active, and eventually reinitiate proliferation enables cancer cell survival and results in observed therapy resistant recurrence (Pienta et al, 2020c(Pienta et al, , 2021.…”

“…New evidence suggests that the dormant cancer cell capable of surviving stress by entering a quiescent state is the polyaneuploid cancer cell (PACC) (Lopez-Sánchez et al, 2014;Pienta et al, 2021). PACCs [also referred to as polyploid giant cancer cells (PGCCs), multinucleated cancer cells, blastomere-like cancer cells, and osteoclast-like cancer cells] are enlarged cancer cells that have undergone whole-genome multiplication of their aneuploid genome (Erenpreisa et al, 2000(Erenpreisa et al, , 2008Mosieniak and Sikora, 2010;Zhang et al, 2014Zhang et al, , 2015Fei et al, 2015;Chen et al, 2019;Pienta et al, 2020c).…”

Viewing Cancer Through the Lens of Corruption: Using Behavioral Ecology to Understand Cancer

“…Polyaneuploid cancer cells (PACCs) are a recently discovered form of collusion in cancer. During times of microenvironmental stress, aneuploid cancer cells can fuse together to form PACCs, entering a state of quiescence or reversible therapy-induced senescence to protect their genome and avoid apoptosis (Pienta et al, 2021). Due to their high levels of genomic content, PACCs that enter the cell cycle and divide into non-polyploid cells can produce new phenotypic variants of cancer cells that contribute to cancer heterogeneity and lethality (Bukkuri et al, under review; Bukkuri et al, under preparation).…”