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Functional Dissection of Pancreatic Ductal Adenocarcinoma (PDAC) Progression Through In Vivo, Genome-Wide CRISPR Screening and Multi-Omic Analysis of Eif4G2-Dependent Translational Programs
Functional Dissection of Pancreatic Ductal Adenocarcinoma (PDAC) Progression Through In Vivo, Genome-Wide CRISPR Screening and Multi-Omic Analysis of Eif4G2-Dependent Translational Programs
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202104837
- ISBN
- 9798297957381
- DDC
- 540
- 서명/저자
- Functional Dissection of Pancreatic Ductal Adenocarcinoma (PDAC) Progression Through In Vivo, Genome-Wide CRISPR Screening and Multi-Omic Analysis of Eif4G2-Dependent Translational Programs
- 발행사항
- [Sl] : Columbia University, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 291 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-04, Section: B.
- 주기사항
- Advisor: Chio, Christine.
- 학위논문주기
- Thesis (Ph.D.)--Columbia University, 2025.
- 초록/해제
- 요약Pancreatic ductal adenocarcinoma (PDAC) is marked by early metastatic spread, intrinsic therapy resistance, and pronounced transcriptional plasticity, all of which contribute to its poor prognosis. I conducted an in vivo, genome-wide CRISPR-Cas9 screening to identify genetic regulators of PDAC progression, capturing both primary tumor growth and metastatic outgrowth. Using immunocompetent, syngeneic allograft models in both young and old hosts, I identified a broad set of tumor suppressors and promoters.Among these, Eif4G2, a noncanonical translation initiation factor, emerged as a selective suppressor of aggressive tumor phenotypes. Loss of Eif4G2 led to poorly differentiated tumors with basal-like features, including squamous histology and increased expression of Krt14. To dissect the underlying mechanisms, I integrated RNA sequencing, ribosome profiling, and mass spectrometry-based proteomics in Eif4G2-deficient PDAC cell lines. These analyses revealed transcriptional upregulation of neuronal and basal programs alongside post-transcriptional alterations in a distinct subset of genes. Notably, Pten, Mib1, and Malat1 were translationally dysregulated in the absence of corresponding mRNA-level changes. Pten loss, alone, recapitulated tumor growth acceleration and poor-differentiation status, suggesting its contribution to the overall Eif4G2-deficient state which is dependent on transcriptional and translational modifications.Together, these findings define Eif4G2 as a tumor suppressor that restrains lineage infidelity and phenotypic plasticity in PDAC. More broadly, this work establishes in vivo CRISPR screening as a powerful approach for identifying regulators of tumor cell fate and highlights the role of translational control as a functional axis of PDAC progression.
- 일반주제명
- Chemistry
- 일반주제명
- Biology
- 일반주제명
- Oncology
- 키워드
- Oncogenes
- 키워드
- Immunocompetent
- 키워드
- Proteomics
- 기타저자
- Columbia University Chemistry
- 기본자료저록
- Dissertations Abstracts International. 87-04B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798297957381
■035 ▼a(MiAaPQ)AAI32171665
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a540
■1001 ▼aPowers, Justin Anthony.
■24510▼aFunctional Dissection of Pancreatic Ductal Adenocarcinoma (PDAC) Progression Through In Vivo, Genome-Wide CRISPR Screening and Multi-Omic Analysis of Eif4G2-Dependent Translational Programs
■260 ▼a[Sl]▼bColumbia University▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a291 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-04, Section: B.
■500 ▼aAdvisor: Chio, Christine.
■5021 ▼aThesis (Ph.D.)--Columbia University, 2025.
■520 ▼aPancreatic ductal adenocarcinoma (PDAC) is marked by early metastatic spread, intrinsic therapy resistance, and pronounced transcriptional plasticity, all of which contribute to its poor prognosis. I conducted an in vivo, genome-wide CRISPR-Cas9 screening to identify genetic regulators of PDAC progression, capturing both primary tumor growth and metastatic outgrowth. Using immunocompetent, syngeneic allograft models in both young and old hosts, I identified a broad set of tumor suppressors and promoters.Among these, Eif4G2, a noncanonical translation initiation factor, emerged as a selective suppressor of aggressive tumor phenotypes. Loss of Eif4G2 led to poorly differentiated tumors with basal-like features, including squamous histology and increased expression of Krt14. To dissect the underlying mechanisms, I integrated RNA sequencing, ribosome profiling, and mass spectrometry-based proteomics in Eif4G2-deficient PDAC cell lines. These analyses revealed transcriptional upregulation of neuronal and basal programs alongside post-transcriptional alterations in a distinct subset of genes. Notably, Pten, Mib1, and Malat1 were translationally dysregulated in the absence of corresponding mRNA-level changes. Pten loss, alone, recapitulated tumor growth acceleration and poor-differentiation status, suggesting its contribution to the overall Eif4G2-deficient state which is dependent on transcriptional and translational modifications.Together, these findings define Eif4G2 as a tumor suppressor that restrains lineage infidelity and phenotypic plasticity in PDAC. More broadly, this work establishes in vivo CRISPR screening as a powerful approach for identifying regulators of tumor cell fate and highlights the role of translational control as a functional axis of PDAC progression.
■590 ▼aSchool code: 0054.
■650 4▼aChemistry
■650 4▼aBiology
■650 4▼aOncology
■653 ▼aOncogenes
■653 ▼aPancreatic ductal adenocarcinoma
■653 ▼aTumor suppressors
■653 ▼aImmunocompetent
■653 ▼aProteomics
■690 ▼a0485
■690 ▼a0306
■690 ▼a0992
■71020▼aColumbia University▼bChemistry.
■7730 ▼tDissertations Abstracts International▼g87-04B.
■790 ▼a0054
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17359115▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
