Integrating mathematical modeling with high-throughput imaging explains how polyploid populations behave in nutrient-sparse environments

Gregory J. Kimmel, Mark Dane, Laura M. Heiser, Philipp M. Altrock, Noemi Andor

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how coexisting cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. In this study, we integrate mathematical modeling with microenvironmental perturbation data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations. Subpopulations were defined by their energy efficiency and chemotactic ability. Invasion distance traveled by a homogeneous population was estimated. For heterogeneous populations, results suggest that an imbalance between nutrient efficacy and chemotactic superiority accelerates invasion. Such imbalance will spatially segregate the two populations and only one type will dominate at the invasion front. Only if these two phenotypes are balanced, the two subpopulations compete for the same space, which decelerates invasion. We investigate ploidy as a candidate biomarker of this phenotypic heterogeneity and discuss its potential to inform the dose ofmTORinhibitors (mTOR-I) that can inhibit chemotaxis just enough to facilitate such competition. Significance: This study identifies the double-edged sword of high ploidy as a prerequisite to personalize combination therapies with cytotoxic drugs and inhibitors of signal transduction pathways such as mTOR-Is.

Original languageEnglish (US)
Pages (from-to)5109-5120
Number of pages12
JournalCancer Research
Volume80
Issue number22
DOIs
StatePublished - Nov 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Integrating mathematical modeling with high-throughput imaging explains how polyploid populations behave in nutrient-sparse environments'. Together they form a unique fingerprint.

Cite this