Resource limitation rewires chromosome instability and ploidy evolution across in vitro and in vivo cancer models.

Whole-genome doubling (WGD) and elevated ploidy are pervasive features of cancer that shape chromosomal instability (CIN), therapeutic response, and metastatic fitness. Yet ploidy is strikingly context dependent: many tumors remain near diploid in vivo despite the frequent emergence of highly polyploid states in vitro. Here, we estimate ploidy dependent chromosome missegregation tolerance using a mathematical model calibrated to growth and chromosome number data from matched near diploid and near tetraploid breast cancer cultures and xenografts. The model architecture reflects a tug of war between two opposing selective forces acting on ploidy--resource limitation that caps high ploidy by imposing energetic and biosynthetic costs, and CIN that can favor higher ploidy by buffering the fitness impact of chromosome gains and losses. The fitted model reproduced chromosome losses in 4N cultures and WGD followed by chromosome losses in 2N cultures. In vivo, the strongest determinants of ploidy shifted from stress associated death at low oxygen to baseline missegregation at higher oxygen. Joint calibration to both in vivo and in vitro contexts assigned tumors lower proliferation, an approximately tenfold higher stress-associated death scale, and an 11-16 fold larger maximal stress induced missegregation increment than cultures. Simulating populations across combinations of constant oxygen levels and missegregation settings showed that ploidy increased with oxygen under conditions supporting population growth. In both culture and tumors, mean ploidy above tetraploidy was associated with population decline. Together, the framework predicts when resource constraints favor chromosome loss and when missegregation tolerance permits high ploidy expansion, providing testable expectations for how CIN perturbations reshape ploidy evolution in different resource environments.