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.

Keywords: drug resistance; evolution; metastasis; tumor microenvironment; whole-genome doubling.

Fig. 1.

The ability to access polyploid programs enables therapeutic resistance, the hallmark of lethal cancer. The PACC theory of cancer recurrence accounts for the ubiquity of recurrence in three steps. First, a few tumor cells respond to stress, e.g., chemotherapy or metabolic stress as a consequence of uncontrolled growth, through a polyploid program and form PACCs. Second, as part of cell enlargement and the polyploid program, PACCs pause proliferation, allowing adaptation to toxic environments while protecting DNA. This state is also associated with motility, which further enables metastasis. Third, when the stimulus is a therapy and is removed, the PACC can undergo depolyploidization, reinitiating tumor cell proliferation and recurrence.

Fig. 2.

Polyaneuploid cancer cells (PACCs). PACCs are observed in many cell lines. Prostate cancer cell line PC3 as an example before (A.1) and at 72 h after treatment with 10 nM docetaxel (A.2). They are also found in animal models (B: PC3 xenograft, 200,000 PC3 cells were injected s.c. in an NSG mouse; tumors were harvested on day 21 and processed for H&E [PACCs circled]) and in patients (C: lung metastasis from a patient with castrate-resistant prostate cancer stained with EpCAM).