Exploring the functional consequences of whole-genome duplication in tumor progression

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Alvarez, James V

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Newcomb, Rachel Leanne

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2022-02-11T21:38:23Z

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2022-02-11T21:38:23Z

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2021

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Genetics and Genomics

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Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome. These events commonly occur during the evolution of human tumors across tissue types and mutational drivers, affecting an estimated 30-37% of all tumors. 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. The polyploidization of a normally diploid cells often compromises genomic stability. In this way, WGD may be capable of promoting tumor formation, growth and progression, by facilitating the evolution of genetic heterogeneity on which selection can act. However, while some features of polyploidy can promote tumor growth, these features can also be countered by associated tumor suppressive qualities of polyploidization and associated cellular stresses. Chromosomal instability and resulting aneuploidy often have negative effects on cellular fitness; this can occur through the induction of proteotoxic stress, replication stress and delayed proliferation. Polyploidization can also be opposed by cell intrinsic and extrinsic pathways, including p53, the Hippo pathway and immunosurveillance. How these diverse and multifaceted features of polyploid cells work together to regulate 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 rates of 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, tumor growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. Our 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.

While our results revealed fitness disadvantages for recurrent polyploid tumor cells, the paradox remains that WGD is common in cancer cells despite this, suggesting that cells must evolve ways to overcome barriers to tumorigenesis. These findings suggest that a polyploid cancer cell may be delicately balanced, relying on certain pathways or processes to compensate for its cellular deficiencies more than their diploid counterparts. Ploidy-specific lethality describes the phenomenon in which inhibiting the activity or expression of a specific protein results in death of polyploid cells but not their diploid counterparts. To interrogate this idea, we next employed our models of recurrent polyploid cells to explore the impact of polyploidization on gene expression and signaling dependencies. Using RNA sequencing we uncovered that tetraploid cells exhibited decreased expression of genes of the cGAS-STING pathway. We performed two loss-of-function CRISPR screens against the kinome, one in vitro and one in vivo, to identify ploidy-specific lethal genes. The in vivo screen revealed candidates for ploidy-specific lethal genes including Srpk1, Mark4 and Ryk. Together these results demonstrated that polyploid recurrent tumor cells exhibit unique gene expression patterns that may reflect selection pressure of the immune system and may rely on unique survival mechanisms in vivo.

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https://hdl.handle.net/10161/24357

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Oncology

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Cellular biology

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Biology

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aneuploidy

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breast cancer

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chromosomal instability

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polyploidy

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tumor recurrence

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whole-genome duplication

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Exploring the functional consequences of whole-genome duplication in tumor progression

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Dissertation

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