A mathematical investigation of polyaneuploid cancer cell memory and cross-resistance in state-structured cancer populations

Summary, in English

The polyaneuploid cancer cell (PACC) state promotes cancer lethality by contributing to survival in extreme conditions and metastasis. Recent experimental evidence suggests that post-therapy PACC-derived recurrent populations display cross-resistance to classes of therapies with independent mechanisms of action. We hypothesize that this can occur through PACC memory, whereby cancer cells that have undergone a polyaneuploid transition (PAT) reenter the PACC state more quickly or have higher levels of innate resistance. In this paper, we build on our prior mathematical models of the eco-evolutionary dynamics of cells in the 2N+ and PACC states to investigate these two hypotheses. We show that although an increase in innate resistance is more effective at promoting cross-resistance, this trend can also be produced via PACC memory. We also find that resensitization of cells that acquire increased innate resistance through the PAT have a considerable impact on eco-evolutionary dynamics and extinction probabilities. This study, though theoretical in nature, can help inspire future experimentation to tease apart hypotheses surrounding how cross-resistance in structured cancer populations arises.

• Author: Anuraag Bukkuri; Kenneth J. Pienta; Robert H. Austin; Emma U. Hammarlund; Sarah R. Amend; Joel S. Brown
• Department/s: Molecular Evolution; LUCC: Lund University Cancer Centre; StemTherapy: National Initiative on Stem Cells for Regenerative Therapy; EpiHealth: Epidemiology for Health
• Publishing year: 2023-12
• Language: English
• Publication/Series: Scientific Reports
• Volume: 13
• Issue: 1
• Links: http://dx.doi.org/10.1038/s41598-023-42368-8
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Cell and Molecular Biology
• Status: Published
• Research group: Molecular Evolution
• ISBN/ISSN/Other: ISSN: 2045-2322