Abstract
Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.
Highlights
Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer
Retrospective analysis of tumors binned as polyploid or diploid showed no difference in time to tumor recurrence (Supplemental Fig. 1 D and G; log-rank test, p = 0.606; Hazards Ratio = 0.66). These results demonstrate that a subset of recurrent tumors are composed of tetraploid tumor cells, indicating that a whole-genome duplication event occurs during the process of tumor recurrence
We found that multiple tumor cell cultures derived from independent primary MTB;TAN tumors rapidly became dominated by tetraploid tumor cells (Supplemental Fig. 4A and B), in spite of the fact that we never observed tetraploid cells in primary tumors in vivo
Summary
Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. Using a genetically engineered mouse model of Her2driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. The prevalence of WGD in cancer, and its association with poor patient outcomes, underscores the need for better understanding how duplication of the cancer genome alters the biology of cancer cells to promote tumor progression. The effects of WGD on cancer cells, and by extension on tumor evolution, are likely shaped by the context in which these events occur. Understanding these context-dependent effects of WGD would benefit from experimental models that mimic human cancers in undergoing WGD during tumor progression. Through a series of in vivo and in vitro experiments, we explore the cellular effects of WGD and its consequences on tumor growth and recurrence
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