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Single-Nucleus Multi-Omic Investigations Resolve and Identify Novel Features of Fibrolamellar Carcinoma
Single-Nucleus Multi-Omic Investigations Resolve and Identify Novel Features of Fibrolamellar Carcinoma
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211152713
- ISBN
- 9798384053279
- DDC
- 575
- 서명/저자
- Single-Nucleus Multi-Omic Investigations Resolve and Identify Novel Features of Fibrolamellar Carcinoma
- 발행사항
- [Sl] : Cornell University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 135 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Sethupathy, Praveen.
- 학위논문주기
- Thesis (Ph.D.)--Cornell University, 2024.
- 초록/해제
- 요약In 2010, the World Health Organization designated fibrolamellar carcinoma (FLC) as a distinct and rare form of rapidly metastasizing liver cancer that predominately afflicts adolescents and young adults. There is no standard therapy for patients with unresectable disease. Thus, there is a dire need to identify therapeutic vulnerabilities to guide the development of treatments.FLC has a low mutational burden, with the only known highly recurrent mutation being a ~400kb spontaneous, heterozygous, somatic deletion on chromosome 19. This deletion results in the chimeric protein DNAJB1-PRKACA (DP), which is sufficient for tumor initiation and progression and necessary for tumor maintenance. Research into pharmacological or siRNA suppression of DP is ongoing. However, due to off-target effects on wild-type PKA, it is imperative to characterize downstream mediators of DP.Multiple studies have been conducted, querying nascent RNA transcription, steady-state mRNA expression, immune cells, and non-coding RNAs such as micro and long non-coding RNAs in FLC. A salient limitation of these studies is the utilization of FLC models that only partially recapitulate FLC tumor biology or rely on bulk sequencing assays that fail to resolve tumor heterogeneity. FLC tumors are heterogeneous, comprising epithelial, endothelial, stromal, and various immune cells. We hypothesize FLC exhibits heterogeneity in its genetics, chromatin accessibility, transcription logic, and tumor microenvironment. A major knowledge gap is understanding the cell types in which these features and processes are active.To bridge this knowledge gap, in my doctoral research I conducted a multi-omic study using single-cell technology to resolve FLC tumor cellular and molecular heterogeneity. Utilizing single-nucleus assay for transposase-accessible chromatin sequencing and single-nucleus RNA sequencing, this study not only corroborated and resolved previous FLC findings but also expanded our knowledge, inferring the single-cell super-enhancer landscape, reporting novel putative transcription factor networks, and detailing the tumor microenvironment. Together, I present a comprehensive genomics analysis describing FLC tumor biology.In summary, this dissertation highlights the importance of elucidating FLC heterogeneity. My research has offered valuable insights into FLC's cellular and molecular underpinnings and identified new therapeutic targets. This work lays the foundation for future investigations toward the development of novel and effective treatments for FLC patients.
- 일반주제명
- Genetics
- 일반주제명
- Oncology
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Immunology
- 키워드
- Genomics
- 키워드
- Pediatric cancer
- 기타저자
- Cornell University Genetics Genomics and Development
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798384053279
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a575
■1001 ▼aFarghli, Alaa Richard.▼0(orcid)0000-0001-5485-1423
■24510▼aSingle-Nucleus Multi-Omic Investigations Resolve and Identify Novel Features of Fibrolamellar Carcinoma
■260 ▼a[Sl]▼bCornell University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a135 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Sethupathy, Praveen.
■5021 ▼aThesis (Ph.D.)--Cornell University, 2024.
■520 ▼aIn 2010, the World Health Organization designated fibrolamellar carcinoma (FLC) as a distinct and rare form of rapidly metastasizing liver cancer that predominately afflicts adolescents and young adults. There is no standard therapy for patients with unresectable disease. Thus, there is a dire need to identify therapeutic vulnerabilities to guide the development of treatments.FLC has a low mutational burden, with the only known highly recurrent mutation being a ~400kb spontaneous, heterozygous, somatic deletion on chromosome 19. This deletion results in the chimeric protein DNAJB1-PRKACA (DP), which is sufficient for tumor initiation and progression and necessary for tumor maintenance. Research into pharmacological or siRNA suppression of DP is ongoing. However, due to off-target effects on wild-type PKA, it is imperative to characterize downstream mediators of DP.Multiple studies have been conducted, querying nascent RNA transcription, steady-state mRNA expression, immune cells, and non-coding RNAs such as micro and long non-coding RNAs in FLC. A salient limitation of these studies is the utilization of FLC models that only partially recapitulate FLC tumor biology or rely on bulk sequencing assays that fail to resolve tumor heterogeneity. FLC tumors are heterogeneous, comprising epithelial, endothelial, stromal, and various immune cells. We hypothesize FLC exhibits heterogeneity in its genetics, chromatin accessibility, transcription logic, and tumor microenvironment. A major knowledge gap is understanding the cell types in which these features and processes are active.To bridge this knowledge gap, in my doctoral research I conducted a multi-omic study using single-cell technology to resolve FLC tumor cellular and molecular heterogeneity. Utilizing single-nucleus assay for transposase-accessible chromatin sequencing and single-nucleus RNA sequencing, this study not only corroborated and resolved previous FLC findings but also expanded our knowledge, inferring the single-cell super-enhancer landscape, reporting novel putative transcription factor networks, and detailing the tumor microenvironment. Together, I present a comprehensive genomics analysis describing FLC tumor biology.In summary, this dissertation highlights the importance of elucidating FLC heterogeneity. My research has offered valuable insights into FLC's cellular and molecular underpinnings and identified new therapeutic targets. This work lays the foundation for future investigations toward the development of novel and effective treatments for FLC patients.
■590 ▼aSchool code: 0058.
■650 4▼aGenetics
■650 4▼aOncology
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aImmunology
■653 ▼aFibrolamellar carcinoma
■653 ▼aGenomics
■653 ▼aMulti-omic investigations
■653 ▼aPediatric cancer
■653 ▼aSingle-cell sequencing
■690 ▼a0369
■690 ▼a0992
■690 ▼a0379
■690 ▼a0982
■690 ▼a0307
■71020▼aCornell University▼bGenetics, Genomics and Development.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0058
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17163476▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
