자료유형  

 학위논문

Control Number  

0017163014

International Standard Book Number  

9798384075493

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Montoya, Tonatiuh.

Publication, Distribution, etc. (Imprint  

[S.l.] : University of California, San Francisco., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

82 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-03, Section: B.

General Note  

Advisor: Willenbring, Holger.

Dissertation Note  

Thesis (Ph.D.)--University of California, San Francisco, 2024.

Summary, Etc.  

요약Liver cancer remains a leading cause of cancer-related death in part due to the shortage of effective therapies, and MYC overexpression defines an aggressive and difficult to treat subset of liver cancer cases. Given MYC's ability to reprogram cellular metabolism and the liver's role in systemic metabolism, we hypothesized that MYC could induce tumor-specific metabolic dependencies that could be targeted to slow tumor growth. We used mass-spectrometry to identify alanine depletion as a conserved metabolic signature of both mouse and human liver tumors. In vitro cell culture and high-content microscopy experiments showed that alanine could promote the proliferation and survival of MYC-overexpressing liver cancer lines in low nutrient conditions. Mechanistically, we found that MYC driven liver cancer cell lines and tumors specifically express the alanine enzyme GPT2, and loss-of-function RNA interference studies confirmed that GPT2 was required for the ability of liver cancer lines to use alanine to proliferate in vitro. We then used a conditional GPT2 knockout mouse to show that GPT2 played a necessary role in MYC-driven liver tumorigenesis in vivo. Isotope tracing and metabolomics were used to identify the TCA cycle, amino acid synthesis, and nucleotide synthesis as metabolic pathways that were fueled downstream of alanine. Finally, we found that L-Cycloserine, an orally bioavailable compound that inhibits GPT2, was efficacious at slowing liver tumor growth in both mouse and human liver cancer models. Thus, we identify a targetable metabolic pathway that MYC-driven liver tumors repurpose to fuel their survival.

Subject Added Entry-Topical Term  

Molecular biology.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Oncology.

Index Term-Uncontrolled  

Alanine

Index Term-Uncontrolled  

Liver cancer

Index Term-Uncontrolled  

Cellular metabolism

Index Term-Uncontrolled  

MYC overexpression

Index Term-Uncontrolled  

Therapy

Added Entry-Corporate Name  

University of California, San Francisco Biomedical Sciences

Host Item Entry  

Dissertations Abstracts International. 86-03B.

Electronic Location and Access  

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Control Number  

joongbu:657683