Metabolic reprogramming during breast cancer progression
Abstract/Contents
- Abstract
- Cancer cells exhibit altered nutrient requirements and utilization compared to normal cells. A comprehensive understanding of the causes and consequences of these altered metabolic features can help inform the development of novel therapeutics aimed at impairing cancer cell proliferation and promoting differentiation, in addition to enriching our understanding of how cancer comes to be. In this thesis, we utilized breast cancer as a model to study how altered cell metabolism relates to differences in proliferative capacity and cell lineage identity. Using a targeted metabolomics approach, we discovered a metabolic signature suggestive of elevated serine and one-carbon (1C) unit metabolism in the aggressive, tissue-tropic metastatic subpopulations of triple-negative breast cancer cells. In line with previous reports, we confirmed a role for the oncogene c-Myc in driving the enhanced proliferation of the metastatic subclones compared to parental cells. Functional validation using genetic and pharmacologic inhibition approaches uncovered an exquisite dependency of metastatic cells on this mitochondrial pathway for growth in vitro and in vivo. Analyses of human breast cancer patient data further identified a significant association between high expression of mitochondrial serine and 1C unit pathway genes with patient mortality. In follow-up work, we determined that low serine levels drives a metabolic signature associated with breast cancer cell aggressiveness characterized by the transcriptional induction of genes involved in de novo serine synthesis and mitochondrial serine and 1C unit metabolism. A global transcriptome analysis uncovered serine starvation-mediated repression of estrogen receptor (ER) signaling in ER+ breast cancer cells, effectively converting them to an ER-- like state. Metabolomics, isotope tracing, and chromatin immunoprecipitation assays revealed a defect in glucose-derived central carbon flux leading to a loss of histone acetylation and silencing of ER pathway genes. Acetate supplementation rescued histone hypoacetylation and ER pathway activity, demonstrating that serine starvation influences breast cancer cell state through a metabolic and epigenetic regulatory axis.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Li, Albert Mao |
|---|---|
| Degree supervisor | Rankin, Erinn |
| Degree supervisor | Ye, Jiangbin |
| Thesis advisor | Rankin, Erinn |
| Thesis advisor | Ye, Jiangbin |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Oro, Anthony, 1958- |
| Thesis advisor | Plevritis, Sylvia |
| Degree committee member | Gozani, Or Pinchas |
| Degree committee member | Oro, Anthony, 1958- |
| Degree committee member | Plevritis, Sylvia |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Albert M. Li. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/hb016hv6035 |
Access conditions
- Copyright
- © 2022 by Albert Mao Li
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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