Abstract
Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Progression is accompanied by a switch to an invasive cell phenotype. Nutrient-limiting environments promote chemotaxis with aggressive morphologies characteristic of invasion. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. We integrate mathematical modeling with microenvironmental perturbation-data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations. Hereby, subpopulations are defined by their energy efficiency and chemotactic ability. We estimate the invasion-distance traveled by a homogeneous population. For heterogeneous populations, our 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 do the two subpopulations compete for the same space, which decelerates invasion. We investigate ploidy as a candidate biomarker of this phenotypic heterogeneity to discern circumstances when inhibiting chemotaxis amplifies internal competition and decelerates tumor progression, from circumstances that render clinical consequences of chemotactic inhibition unfavorable.
Significance A better understanding of the nature of the double-edged sword of high ploidy is a prerequisite to personalize combination-therapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Financial support, This work was supported by the National Cancer Institute R00CA215256 awarded to NA. PMA acknowledges support through the National Cancer Institute, part of the National Institutes of Health (NIH), under grant number P30-CA076292. LH acknowledges support through NIH research grants 1U54CA209988, U54-HG008100, Jayne Koskinas Ted Giovanis Foundation for Health and Policy, and Breast Cancer Research Foundation.
Conflict of Interest, The authors declare no potential conflicts of interest.
↵* Noemi Andor; Moffitt Cancer Center, SRB 23224 B2 3011 Holly Drive, 33612 Tampa; noemi.andor{at}moffitt.org