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Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer
Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152124
- ISBN
- 9798384075493
- DDC
- 574
- 서명/저자
- Alanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer
- 발행사항
- [Sl] : University of California, San Francisco, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 82 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Willenbring, Holger.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2024.
- 초록/해제
- 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.
- 일반주제명
- Molecular biology
- 일반주제명
- Cellular biology
- 일반주제명
- Oncology
- 키워드
- Alanine
- 키워드
- Liver cancer
- 키워드
- Therapy
- 기타저자
- University of California, San Francisco Biomedical Sciences
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211152124
■006m o d
■007cr#unu||||||||
■020 ▼a9798384075493
■035 ▼a(MiAaPQ)AAI31482294
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aMontoya, Tonatiuh.▼0(orcid)0000-0002-5543-7838
■24510▼aAlanine Catabolism as a Targetable Vulnerability for MYC-Driven Liver Cancer
■260 ▼a[Sl]▼bUniversity of California, San Francisco▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a82 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Willenbring, Holger.
■5021 ▼aThesis (Ph.D.)--University of California, San Francisco, 2024.
■520 ▼aLiver 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.
■590 ▼aSchool code: 0034.
■650 4▼aMolecular biology
■650 4▼aCellular biology
■650 4▼aOncology
■653 ▼aAlanine
■653 ▼aLiver cancer
■653 ▼aCellular metabolism
■653 ▼aMYC overexpression
■653 ▼aTherapy
■690 ▼a0307
■690 ▼a0379
■690 ▼a0992
■71020▼aUniversity of California, San Francisco▼bBiomedical Sciences.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0034
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163014▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
