자료유형  

 학위논문

Control Number  

0016934427

International Standard Book Number  

9798380273053

Dewey Decimal Classification Number  

519.93

Main Entry-Personal Name  

Li, Albert M.

Publication, Distribution, etc. (Imprint  

[S.l.] : Stanford University., 2022

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2022

Physical Description  

1 online resource(208 p.)

General Note  

Source: Dissertations Abstracts International, Volume: 85-03, Section: B.

General Note  

Advisor: Gozani, Or Pinchas;Oro, Anthony;Plevritis, Sylvia.

Dissertation Note  

Thesis (Ph.D.)--Stanford University, 2022.

Restrictions on Access Note  

This item must not be sold to any third party vendors.

Summary, Etc.  

요약Cancer 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 cMyc 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 novoserine 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.

Subject Added Entry-Topical Term  

Control theory.

Subject Added Entry-Topical Term  

Metastasis.

Subject Added Entry-Topical Term  

Mutation.

Subject Added Entry-Topical Term  

Genetics.

Subject Added Entry-Topical Term  

Hypoxia.

Subject Added Entry-Topical Term  

Amino acids.

Subject Added Entry-Topical Term  

Mitochondria.

Subject Added Entry-Topical Term  

Biology.

Subject Added Entry-Topical Term  

Metabolism.

Subject Added Entry-Topical Term  

Epigenetics.

Subject Added Entry-Topical Term  

Respiration.

Subject Added Entry-Topical Term  

Breast cancer.

Subject Added Entry-Topical Term  

Signal transduction.

Subject Added Entry-Topical Term  

Oxidation.

Subject Added Entry-Topical Term  

Carbon.

Subject Added Entry-Topical Term  

Engineering.

Subject Added Entry-Topical Term  

Tumors.

Subject Added Entry-Topical Term  

Cell growth.

Subject Added Entry-Topical Term  

Enzymes.

Subject Added Entry-Topical Term  

Metabolites.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Oncology.

Subject Added Entry-Topical Term  

Systems science.

Added Entry-Corporate Name  

Stanford University.

Host Item Entry  

Dissertations Abstracts International. 85-03B.

Host Item Entry  

Dissertation Abstract International

Electronic Location and Access  

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Control Number  

joongbu:642073