Metabolic Adaptations in Tumor Recurrence

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Alvarez, James V

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Fox, Douglas B

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2021-01-12T22:25:22Z

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2023-01-11T09:17:29Z

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2020

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Molecular Cancer Biology

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The survival and eventual recurrence of dormant residual tumor cells following therapy is a leading cause of death in many tumor types. The metabolic properties of dormant residual tumor cells, which are thought to be quiescent or slowly proliferating, are likely distinct from those of rapidly growing tumors. However, it is not known whether alterations in cellular metabolism directly regulate the survival of dormant cells or their reactivation to form recurrent tumors. To address this, we used a conditional mouse model of Her2-driven breast cancer to study metabolic adaptations following Her2 inhibition, during dormancy, and after tumor recurrence. First, we found that Her2 downregulation caused widespread changes in cellular metabolism, culminating in oxidative stress. Tumor cells adapted to this metabolic stress by upregulation of the antioxidant transcription factor, NRF2. Constitutive NRF2 expression persisted during dormancy and in recurrent tumors. Constitutive activation of NRF2 accelerated recurrence, while suppression of NRF2 impaired recurrent tumor growth. These results are supported by clinical data showing that the NRF2 transcriptional program is activated in recurrent breast tumors, and that NRF2 is associated with poor prognosis in patients with breast cancer. Mechanistically, NRF2 signaling in recurrent tumors induced metabolic reprogramming to re-establish redox homeostasis and upregulate de novo nucleotide synthesis. An in vivo CRISPR screen identified genes in the redox and nucleotide pathways as the essential downstream mediators of NRF2 in recurrent tumors. The NRF2-driven metabolic state rendered recurrent tumor cells sensitive to glutaminase inhibition, and glutaminase inhibition prevented reactivation of dormant tumor cells, suggesting that NRF2-high dormant and recurrent tumors can be therapeutically targeted. Together, these data provide evidence that NRF2-driven metabolic reprogramming promotes the recurrence of dormant breast cancer. Second, we found that the metabolic enzyme Bcat1 is upregulated in recurrent tumors as a result of epithelial-to-mesenchymal transition. We found that Bcat1 knockout impaired recurrent tumor growth, demonstrating its potential as a therapeutic target for recurrent tumors.

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https://hdl.handle.net/10161/22148

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Pharmacology

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Breast cancer

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Her2

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NRF2

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Tumor dormancy

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Tumor metabolism

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Tumor recurrence

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Metabolic Adaptations in Tumor Recurrence

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Dissertation

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23.934246575342463

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