Poly-aneuploid cancer cells promote evolvability, generating lethal cancer

Abstract

Cancer cells utilize the forces of natural selection to evolve evolvability allowing a constant supply of heritable variation that permits a cancer species to evolutionary track changing hazards and opportunities. Over time, the dynamic tumor ecosystem is exposed to extreme, catastrophic changes in the conditions of the tumor-natural (e.g., loss of blood supply) or imposed (therapeutic). While the nature of these catastrophes may be varied or unique, their common property may be to doom the current cancer phenotype unless it evolves rapidly. Poly-aneuploid cancer cells (PACCs) may serve as efficient sources of heritable variation that allows cancer cells to evolve rapidly, speciate, evolutionarily track their environment, and most critically for patient outcome and survival, permit evolutionary rescue, therapy resistance, and metastasis. As a conditional evolutionary strategy, they permit the cancer cells to accelerate evolution under stress and slow down the generation of heritable variation when conditions are more favorable or when the cancer cells are closer to an evolutionary optimum. We hypothesize that they play a critical and outsized role in lethality by their increased capacity for invasion and motility, for enduring novel and stressful environments, and for generating heritable variation that can be dispensed to their 2N+ aneuploid progeny that make up the bulk of cancer cells within a tumor, providing population rescue in response to therapeutic stress. Targeting PACCs is essential to cancer therapy and patient cure-without the eradication of the resilient PACCs, cancer will recur in treated patients.

Keywords: PGCC; cancer ecology; cancer lethality; cancer speciation; evolvability; metastasis; polyploid giant cancer cell; poly‐aneuploid cancer cell; therapeutic resistance; therapy resistance.

Figure 1

(a and b) Prostate cancer cell line PC3 treated with docetaxel for 6 days shows nearly all surviving cells are PACCs. (a) PACCs indicated by white arrow; non‐PACC indicated by black arrow; (b) shows an identical image with PACCs outlined for clarity (scale = 200 µM). (c) Invasive high grade papillary urothelial carcinoma H&E shows region of focal PACCs (indicated by white arrow)

Figure 2

Using a current standard‐of‐care paradigm, systemic therapies including chemotherapy, radiation, and hormone therapy reduce overall tumor burden, but enrich for PACCs that then eventually give rise to resistant cancer cell population (a). Applying an evolutionary ecology strategy, using standard‐of‐care systemic therapy to enrich for PACCs and then directly targeting their peculiar vulnerabilities (e.g., requirement for centrosome clustering) or better drug delivery due to decreased tumor bulk opens the door for possible cancer cure in treated patients