@article{2b3df571fa7f47c3a26ba3e5312737b1,
title = "Stochastic models of Mendelian and reverse transcriptional inheritance in state-structured cancer populations",
abstract = "Recent evidence suggests that a polyaneuploid cancer cell (PACC) state may play a key role in the adaptation of cancer cells to stressful environments and in promoting therapeutic resistance. The PACC state allows cancer cells to pause cell division and to avoid DNA damage and programmed cell death. Transition to the PACC state may also lead to an increase in the cancer cell{\textquoteright}s ability to generate heritable variation (evolvability). One way this can occur is through evolutionary triage. Under this framework, cells gradually gain resistance by scaling hills on a fitness landscape through a process of mutation and selection. Another way this can happen is through self-genetic modification whereby cells in the PACC state find a viable solution to the stressor and then undergo depolyploidization, passing it on to their heritably resistant progeny. Here, we develop a stochastic model to simulate both of these evolutionary frameworks. We examine the impact of treatment dosage and extent of self-genetic modification on eco-evolutionary dynamics of cancer cells with aneuploid and PACC states. We find that under low doses of therapy, evolutionary triage performs better whereas under high doses of therapy, self-genetic modification is favored. This study generates predictions for teasing apart these biological hypotheses, examines the implications of each in the context of cancer, and provides a modeling framework to compare Mendelian and non-traditional forms of inheritance.",
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/s41598-022-17456-w",
language = "English (US)",
volume = "12",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}