RT Journal Article
SR Electronic
T1 Invasion of homogeneous and polyploid populations in nutrient-limiting environments
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.15.041566
DO 10.1101/2020.04.15.041566
A1 Gregory J. Kimmel
A1 Mark Dane
A1 Laura Heiser
A1 Philipp M. Altrock
A1 Noemi Andor
YR 2020
UL http://biorxiv.org/content/early/2020/04/17/2020.04.15.041566.abstract
AB 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 exhibit chemotaxis with aggressive morphologies characteristic of invasion. The mTOR pathway senses essential nutrients, informing the cell to respond with either increased chemotaxis and nutrient uptake or cell cycle progression. Randomized clinical trials have shown that mTOR inhibitors (mTOR-I) improve the outcome of metastatic breast cancer patients. However, there are considerable differences between and within tumors that impact the effectiveness of mTOR-I, including differences in access to nutrients. 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 modeling with microenvironmental perturbations 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 calculate 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 segregate the two populations spatially and only one type will dominate at the invasion front. Only if these two phenotypes are balanced do the two populations 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 innternal 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 combinationtherapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.Competing Interest StatementThe authors have declared no competing interest.