@article{62ec57c573f043adb162d0182746f2b5,
title = "A life history model of the ecological and evolutionary dynamics of polyaneuploid cancer cells",
abstract = "Therapeutic resistance is one of the main reasons for treatment failure in cancer patients. The polyaneuploid cancer cell (PACC) state has been shown to promote resistance by providing a refuge for cancer cells from the effects of therapy and by helping them adapt to a variety of environmental stressors. This state is the result of aneuploid cancer cells undergoing whole genome doubling and skipping mitosis, cytokinesis, or both. In this paper, we create a novel mathematical framework for modeling the eco-evolutionary dynamics of state-structured populations and use this framework to construct a model of cancer populations with an aneuploid and a PACC state. Using in silico simulations, we explore how the PACC state allows cancer cells to (1) survive extreme environmental conditions by exiting the cell cycle after S phase and protecting genomic material and (2) aid in adaptation to environmental stressors by increasing the cancer cell{\textquoteright}s ability to generate heritable variation (evolvability) through the increase in genomic content that accompanies polyploidization. In doing so, we demonstrate the ability of the PACC state to allow cancer cells to persist under therapy and evolve therapeutic resistance. By eliminating cells in the PACC state through appropriately-timed PACC-targeted therapies, we show how we can prevent the emergence of resistance and promote cancer eradication.",
author = "Anuraag Bukkuri and Pienta, {Kenneth J.} and Austin, {Robert H.} and Hammarlund, {Emma U.} and Amend, {Sarah R.} and Brown, {Joel S.}",
note = "Funding Information: AB acknowledges support by the Stiftelsen L{\"a}ngmanska kulturfonden (BA22-0753), the Royal Swedish Academy of Sciences Stiftelsen GS Magnusons fond (MG2022-0019), the Crafoord foundation (20220633), and the National Science Foundation Graduate Research Fellowship Program under Grant No. 1746051. RAH was supported by the US National Science Foundation PHY-1659940, the National Science Foundation through the Center for the Physics of Biological Function (PHY-1734030), and the Princeton Catalysis Initiative. JSB acknowledges funding from NIH/NCI 1U54CA193489-01A1, Cancer as a Complex Adaptive System, NIH/NCI U54 Supplement, The tumor-host evolutionary arms race, and NIH/NCI 1R01CA258089, Eco-evolutionary drivers of clonal dynamics during UV-induced skin carcinogenesis. EUH received funding from the ParadOX-ERC Starting Grant (No. 96948), the Crafoord foundation (20220633), and from the Swedish Research Council (Grant 2019-05254). SRA was funded by the US Department of Defense CDMRP/PCRP (W81XWH-20-10353), the Patrick C. Walsh Prostate Cancer Research Fund and the Prostate Cancer Foundation. KJP acknowledges funding from NCI grants U54CA143803, CA163124, CA093900, and CA143055, and the Prostate Cancer Foundation. This work was also supported by the William and Carolyn Stutt Research Fund, Ronald Rose, MC Dean, Inc., William and Marjorie Springer, Mary and Dave Stevens, Louis Dorfman, the Jones Family Foundation, Timothy Hanson, and the David and June Trone Family Foundation. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41598-022-18137-4",
language = "English (US)",
volume = "12",
journal = "Scientific reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}